| 1. |
- Li, Tianfeng, et al.
(författare)
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Bruton’s tyrosine kinase potentiates ALK signaling and serves as a potential therapeutic target of neuroblastoma
- 2018
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Ingår i: Oncogene. - : Springer Science and Business Media LLC. - 0950-9232 .- 1476-5594. ; 37:47, s. 6180-6194
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Tidskriftsartikel (refereegranskat)abstract
- Aberrant activation of anaplastic lymphoma kinase (ALK) can cause sporadic and familial neuroblastoma. Using a proteomics approach, we identified Bruton’s tyrosine kinase (BTK) as a novel ALK interaction partner, and the physical interaction was confirmed by co-immunoprecipitation. BTK is expressed in neuroblastoma cell lines and tumor tissues. Its high expression correlates with poor relapse-free survival probability of neuroblastoma patients. Mechanistically, we demonstrated that BTK potentiates ALK-mediated signaling in neuroblastoma, and increases ALK stability by reducing ALK ubiquitination. Both ALKWT and ALKF1174L can induce BTK phosphorylation and higher capacity of ALKF1174L is observed. Furthermore, the BTK inhibitor ibrutinib can effectively inhibit the growth of neuroblastoma xenograft in nude mice, and the combination of ibrutinib and the ALK inhibitor crizotinib further enhances the inhibition. Our study provides strong rationale for clinical trial of ALK-positive neuroblastoma using ibrutinib or the combination of ibrutinib and ALK inhibitors.
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| 2. |
- Sun, Guoqiang, et al.
(författare)
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Low temperature self-healing character of asphalt mixtures under different fatigue damage degrees
- 2019
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Ingår i: Construction and Building Materials. - : ELSEVIER SCI LTD. - 0950-0618 .- 1879-0526. ; 223, s. 870-882
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Tidskriftsartikel (refereegranskat)abstract
- The primary objective of this study is to advance the understanding of the low temperature self-healing character of asphalt mixtures under different damage degrees, thus to determine the effective strategy of asphalt pavement maintenance. Firstly, three kinds of asphalt mixtures are selected to conduct the indirect tensile (IDT) fatigue test to a certain fatigue damage degree at low temperatures, and then the resilient modulus (Mr) at different rest time is measured to quantify the healing potential. Next, the fatigue loading with different intermittent time (0 s, 1 s and 3 s) is applied to determine the impact of intermittent time on healing potential. The results indicate that the descending order of healing potential of asphalt mixtures is: SMA-11 > AC-8 > AC-11 at 5 degrees C and -5 degrees C. The loading intermittent time has an obvious effect on the fatigue damage state of asphalt mixtures, while the longer the intermittent time, the less the effect on fatigue damage healing. Besides, the fatigue damage state has great influence on its healing potential of asphalt mixture. Under the low damage conditions, the initial healing rate is greater than the long term healing rate. However, the low temperature (-5 degrees C) dramatically reduces the healing rate of asphalt mixtures, and causes their long-term healing rate to stabilize gradually to a very low level. Especially under the high fatigue damage conditions, the healing potential of asphalt mixtures will almost disappear at -5 degrees C. Furthermore, together with meso-scale Computed Tomography (CT) scanning technique, it is found that the intemal crack distribution characteristics of different graded asphalt mixtures are different even under the same damage degree, which may explain the differences in the healing potential of asphalt mixtures. The use of a fast two-dimensional (2D) scanning technology further confirms that the crack zones inside the asphalt mixture are gradually shrinking after a period of high temperature healing. Finally, the Grey relational analysis reveals that the healing time has the most significant influence on the healing potential of asphalt mixtures. The gradation type and temperature have the similar influence level on the healing potential. The correlation degree between the fatigue damage degree and healing potential is the smallest compared with the other three factors. All rights reserved.
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| 3. |
- Wang, Chengdong, et al.
(författare)
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The proto-oncogene transcription factor Ets1 regulates neural crest development through Histone Deacetylase 1 to mediate output of bone morphogenetic protein signaling.
- 2015
-
Ingår i: Journal of Biological Chemistry. - 1083-351X. ; 290:36, s. 21925-21938
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Tidskriftsartikel (refereegranskat)abstract
- The neural crest (NC) is a transient, migratory cell population that differentiates into a large variety of tissues including craniofacial cartilage, melanocytes, and peripheral nervous system. NC is initially induced at the border of neural plate and non-neuralectoderm by balanced regulation of multiple signaling pathways, among which an intermediate bone morphogenetic protein (BMP) signaling is essential for NC formation. Ets1, a proto-oncogene playing important roles in tumor invasion, has also been implicated in delamination of NC cells. In this study, we investigated Ets1 function in NC formation using Xenopus. Overexpression of ets1 repressed NC formation through down-regulation of BMP signaling. Moreover, ets1 repressed the BMP-responsive gene id3 that is essential for NC formation. Conversely, overexpression of id3 can partially rescue the phenotype of NC inhibition induced by ectopic ets1. Mechanistically, we found that Ets1 binds to id3 promoter as well as Histone Deacetylase 1 (HDAC1), suggesting that Ets1 recruits HDAC1 to the promoter of id3, thereby inducing Histone deacetylation of the id3 promoter. Thus, our studies indicate that Ets1 regulates NC formation through attenuating BMP signaling epigenetically.
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| 4. |
- Wang, Fang, et al.
(författare)
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Emerging contaminants: A One Health perspective
- 2024
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Ingår i: Innovation. - 2666-6758. ; 5
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Forskningsöversikt (refereegranskat)abstract
- Environmental pollution is escalating due to rapid global development that often prioritizes human needs over planetary health. Despite global efforts to mitigate legacy pollutants, the continuous introduction of new substances remains a major threat to both people and the planet. In response, global initiatives are focusing on risk assessment and regulation of emerging contaminants, as demonstrated by the ongoing efforts to establish the UN's Intergovernmental Science-Policy Panel on Chemicals, Waste, and Pollution Prevention. This review identifies the sources and impacts of emerging contaminants on planetary health, emphasizing the importance of adopting a One Health approach. Strategies for monitoring and addressing these pollutants are discussed, underscoring the need for robust and socially equitable environmental policies at both regional and international levels. Urgent actions are needed to transition toward sustainable pollution management practices to safeguard our planet for future generations.
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| 5. |
- Yang, Anning, et al.
(författare)
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Homocysteine accelerates hepatocyte autophagy by upregulating TFEB via DNMT3b-mediated DNA hypomethylation
- 2023
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Ingår i: Acta Biochimica et Biophysica Sinica. - : China Science Publishing & Media Ltd.. - 1672-9145. ; 55:8, s. 1184-1192
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Tidskriftsartikel (refereegranskat)abstract
- Autophagy plays a critical role in the physiology and pathophysiology of hepatocytes. High level of homocysteine (Hcy) promotes autophagy in hepatocytes, but the underlying mechanism is still unknown. Here, we investigate the relationship between Hcy-induced autophagy level and the expression of nuclear transcription factor EB (TFEB). The results show that Hcy-induced autophagy level is mediated by upregulation of TFEB. Silencing of TFEB decreases the level of autophagy-related protein LC3BII/I and increases p62 expression level in hepatocytes after exposure to Hcy. Moreover, the effect of Hcy on the expression of TFEB is regulated by hypomethylation of the TFEB promoter catalyzed by DNA methyltransferase 3b (DNMT3b). In summary, this study shows that Hcy can activate autophagy by inhibiting DNMT3b-mediated DNA methylation and upregulating TFEB expression. These findings provide another new mechanism for Hcy-induced autophagy in hepatocytes.
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| 6. |
- Bai, Ru, et al.
(författare)
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The NF-κB modulated miR-194-5p/IGF1R/PPFIBP axis is crucial for the tumorigenesis of ovarian cancer
- 2020
-
Ingår i: Journal of Cancer. - : Ivyspring International Publisher. - 1837-9664. ; 11:12, s. 3433-3445
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Tidskriftsartikel (refereegranskat)abstract
- miRNAs are involved in the tumorigenesis of various malignancies. In the current study, we found that miR-194-5p expression is downregulated in ovarian cancer tissues, and downregulation of miR-194-5p expression promotes proliferation, invasion and migration of human ovarian cancer cells in vitro and ovarian tumor growth in nude mice. We further found that IGF1R and PPFIBP are targets of miR-194-5p, and downregulation of miR-194-5p expression increases IGF1R and PPFIBP expression, resulting in increased proliferation, invasion and migration of ovarian cancer cells. Moreover, we showed that NF-κB can bind to the promoter region of miR-194-5p, and negatively regulate the expression of miR-194-5p in ovarian cancer cells. Taken together, our results suggested a NF-κB modulated miR-194-5p/IGF1R/ PPFIBP axis that is crucial for the tumorigenesis of ovarian cancer, which provides a new insight into the development of ovarian cancer.
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| 7. |
- Bai, Ru, et al.
(författare)
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The NF-κB-modulated miR-19a-3p enhances malignancy of human ovarian cancer cells through inhibition of IGFBP-3 expression
- 2019
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Ingår i: Molecular Carcinogenesis. - : Wiley. - 0899-1987 .- 1098-2744. ; 58:12, s. 2254-2265
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Tidskriftsartikel (refereegranskat)abstract
- Ovarian cancer is the most lethal gynecologic malignancy due to the lack of symptoms until advanced stages, and new diagnosis and treatment strategy is in urgent need. In this study, we found higher expression of miR-19a-3p in ovarian cancer tissues compared with that in the adjacent normal tissues. By chromatin immunoprecipitation (ChIP) and electrophoretic mobility shift assay (EMSA) analysis, we showed that nuclear factor-kappaB (NF-κB) binds to the promoter of miR-19a-3p, leading to reduced expression in ovarian cancer cells. Further study indicated that miR-19a-3p inhibits the expression of insulin-like growth factor binding protein-3 (IGFBP-3), resulting in enhanced growth and migration of ovarian cancer cells in vitro and tumor growth in vivo. These results showed that miR-19a-3p enhances the oncogenesis of ovarian cancer through inhibition of IGFBP-3 expression, and which can be inhibited by NF-κB, suggesting an NF-κB/miR-19a-3p/IGFBP-3 pathway in the oncogenesis of ovarian cancer, which expands our understanding of ovarian cancer and they may contribute to the development of new diagnosis and treatment of ovarian cancer.
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| 8. |
- Chen, Hongxia, et al.
(författare)
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PRL2 Phosphatase Promotes Oncogenic KIT Signaling in Leukemia Cells through Modulating CBL Phosphorylation
- 2024
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Ingår i: Molecular Cancer Research. - 1541-7786. ; 22:1, s. 94-103
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Tidskriftsartikel (refereegranskat)abstract
- Receptor tyrosine kinase KIT is frequently activated in acute myeloid leukemia (AML). While high PRL2 (PTP4A2) expression is correlated with activation of SCF/KIT signaling in AML, the underlying mechanisms are not fully understood. We discovered that inhibition of PRL2 significantly reduces the burden of oncogenic KIT-driven leukemia and extends leukemic mice survival. PRL2 enhances oncogenic KIT signaling in leukemia cells, promoting their proliferation and survival. We found that PRL2 dephosphorylates CBL at tyrosine 371 and inhibits its activity toward KIT, leading to decreased KIT ubiquitination and enhanced AKT and ERK signaling in leukemia cells.
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| 9. |
- Dong, Mei, et al.
(författare)
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Cold Exposure Promotes Atherosclerotic Plaque Growth and Instability via UCP1-Dependent Lipolysis
- 2013
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Ingår i: Cell Metabolism. - : Elsevier (Cell Press). - 1550-4131 .- 1932-7420. ; 18:1, s. 118-129
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Tidskriftsartikel (refereegranskat)abstract
- Molecular mechanisms underlying the cold-associated high cardiovascular risk remain unknown. Here, we show that the cold-triggered food-intake-independent lipolysis significantly increased plasma levels of small low-density lipoprotein (LDL) remnants, leading to accelerated development of atherosclerotic lesions in mice. In two genetic mouse knockout models (apolipoprotein E-/- [ApoE(-/-)] and LDL receptor(-/-) [Ldlr(-/-)] mice), persistent cold exposure stimulated atherosclerotic plaque growth by increasing lipid deposition. Furthermore, marked increase of inflammatory cells and plaque-associated microvessels were detected in the cold-acclimated ApoE(-/-) and Ldlr(-/-) mice, leading to plaque instability. Deletion of uncoupling protein 1 (UCP1), a key mitochondrial protein involved in thermogenesis in brown adipose tissue (BAT), in the ApoE(-/-) strain completely protected mice from the cold-induced atherosclerotic lesions. Cold acclimation markedly reduced plasma levels of adiponectin, and systemic delivery of adiponectin protected ApoE(-/-) mice from plaque development. These findings provide mechanistic insights on low-temperature-associated cardiovascular risks.
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| 10. |
- Heiss, Elke, et al.
(författare)
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Identification of Y589 and Y599 in the juxamembrane domain of Flt3 as ligand-induced autophosphorylation sites involved in binding of Src family kinases and the protein tyrosine phosphatase SHP2
- 2006
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 108:5, s. 1542-1550
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Tidskriftsartikel (refereegranskat)abstract
- Early signal relay steps upon ligand binding to the receptor tyrosine kinase Flt3, i.e. sites of Flt3 autophosphorylation and subsequent docking partners, are mainly unresolved. By immunoprecipitation of specific tryptic peptides contained in the juxtamembrane region of human Flt3 and subsequent radiosequencing we identified the tyrosine residues 572, 589, 591 and 599 as in vivo autophosphorylation sites. Focusing on Y589 and Y599, we examined Flt3-ligand-mediated responses in WT-Flt3-, Y589F-Flt3- and Y599F-Flt3-expressing 32D cells. Compared to WT-Flt3-32D cells upon ligand-stimulation, 32DY589F- Flt3 showed enhanced Erk activation and proliferation/survival whereas 32DY599F-Flt3 cells hereby displayed substantially diminished responses. Both pY589 and pY599 were identified as association sites for signal relay molecules including Src family kinases and SHP2. Consistently, 32D-Y589F-Flt3 and 32D-Y599F-Flt3 showed decreased FL-triggered activation of Src family kinases. Interference with the Srcdependent negative regulation of Flt3 signaling may account for the enhanced mitogenic response of Y589F-Flt3. Y599 was additionally found to interact with the protein tyrosine phosphatase SHP2 in a phosphorylation dependent manner. As Y599F-Flt3-32D was unable to associate with and to phosporylate SHP2 and since silencing of SHP2 in WT-Flt3-expressing cells mimicked the Y599F-Flt3-phenotype we hypothesize that recruitment of SHP2 to pY599 contributes to FL-mediated Erk activation and proliferation.
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| 11. |
- Kabir, Nuzhat N., et al.
(författare)
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SOCS6 is a selective suppressor of receptor tyrosine kinase signaling
- 2014
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Ingår i: Tumor Biology. - : Springer Science and Business Media LLC. - 1423-0380 .- 1010-4283. ; 35:11, s. 10581-10589
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Forskningsöversikt (refereegranskat)abstract
- The suppressors of cytokine signaling (SOCS) are well-known negative regulators of cytokine receptor signaling. SOCS6 is one of eight members of the SOCS family of proteins. Similar to other SOCS proteins, SOCS6 consists of an uncharacterized extended N-terminal region followed by an SH2 domain and a SOCS box. Unlike other SOCS proteins, SOCS6 is mainly involved in negative regulation of receptor tyrosine kinase signaling. SOCS6 is widely expressed in many tissues and is found to be downregulated in many cancers including colorectal cancer, gastric cancer, lung cancer, ovarian cancer, stomach cancer, thyroid cancer, hepatocellular carcinoma, and pancreatic cancer. SOCS6 is involved in negative regulation of receptor signaling by increasing degradation mediated by ubiquitination of receptors or substrate proteins and induces apoptosis by targeting mitochondrial proteins. Therefore, SOCS6 turns out as an important regulator of survival signaling and its activity is required for controlling receptor tyrosine kinase signaling.
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| 12. |
- Kazi, Julhash U, et al.
(författare)
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ABL2 suppresses FLT3-ITD-induced cell proliferation through negative regulation of AKT signaling
- 2017
-
Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 8:7, s. 12194-12202
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Tidskriftsartikel (refereegranskat)abstract
- The type III receptor tyrosine kinase FLT3 is one of the most commonly mutated oncogenes in acute myeloid leukemia (AML). Inhibition of mutated FLT3 in combination with chemotherapy has displayed promising results in clinical trials. However, one of the major obstacles in targeting FLT3 is the development of resistant disease due to secondary mutations in FLT3 that lead to relapse. FLT3 and its oncogenic mutants signal through associating proteins that activate downstream signaling. Thus, targeting proteins that interact with FLT3 and their downstream signaling cascades can be an alternative approach to treat FLT3-dependent AML. We used an SH2 domain array screen to identify novel FLT3 interacting proteins and identified ABL2 as a potent interacting partner of FLT3. To understand the role of ABL2 in FLT3-mediated biological and cellular events, we used the murine pro-B cell line Ba/F3 as a model system. Overexpression of ABL2 in Ba/F3 cells expressing an oncogenic mutant of FLT3 (FLT3-ITD) resulted in partial inhibition of FLT3-ITD-dependent cell proliferation and colony formation. ABL2 expression did not alter the kinase activity of FLT3, its ubiquitination or its stability. However, it partially blocked FLT3-induced AKT phosphorylation without affecting ERK1/2 and p38 activation. Taken together our data suggest that ABL2 acts as negative regulator of signaling downstream of FLT3.
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| 13. |
- Kazi, Julhash U., et al.
(författare)
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Fluorescence-Activated Cell Sorting
- 2015
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Ingår i: The SAGE Encyclopedia of Stem Cell Research. - 2455 Teller Road, Thousand Oaks California 91320 : SAGE Publications, Inc. - 9781483347660 - 9781483347684 ; , s. 418-420
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Bokkapitel (övrigt vetenskapligt/konstnärligt)
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| 14. |
- Kazi, Julhash U., et al.
(författare)
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Src-Like Adaptor Protein (SLAP) differentially regulates normal and oncogenic c-Kit signaling
- 2014
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Ingår i: Journal of Cell Science. - : The Company of Biologists. - 0021-9533 .- 1477-9137. ; 127:3, s. 653-662
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Tidskriftsartikel (refereegranskat)abstract
- The Src-Like Adaptor Protein (SLAP) is an adaptor protein sharing considerable structural homology with Src. SLAP is expressed in variety of cells regulating receptor tyrosine kinase signaling by direct association. In this report, we show that SLAP associates with both wild-type and oncogenic c-Kit (c-Kit-D816V). The association involves SLAP SH2 domain and receptor phosphotyrosine residues different from those mediating Src interaction. Association of SLAP triggers c-Kit ubiquitination which, in turn, is followed by receptor degradation. Although SLAP depletion potentiates c-Kit downstream signaling by stabilizing the receptor, it remains non-functional in c-Kit-D816V signaling. Ligand-stimulated c-Kit or c-Kit-D816V did not alter membrane localization of SLAP. Interestingly oncogenic c-Kit-D816V, but not wild-type c-Kit, phosphorylates SLAP on Y120, Y258 and Y273 residues. Physical interaction between c-Kit-D816V and SLAP is mandatory for the phosphorylation to take place. Although tyrosine phosphorylated SLAP does not affect c-Kit-D816V signaling, mutation of these tyrosine sites to phenylalanine can restore SLAP activity. Taken together the data demonstrate that SLAP negatively regulates wild-type c-Kit signaling, but not its oncogenic counterpart, indicating a possible mechanism by which the oncogenic c-Kit bypasses the normal cellular negative feedback control.
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| 15. |
- Kazi, Julhash U., et al.
(författare)
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Suppressor Of cytokine signaling 6 (SOCS6) negatively regulates Flt3 signal transduction through direct binding to phosphorylated Tyr 591 and Tyr 919 of Flt3.
- 2012
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Ingår i: Journal of Biological Chemistry. - 1083-351X. ; 287:43, s. 36509-36517
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Tidskriftsartikel (refereegranskat)abstract
- The receptor tyrosine kinase Flt3 is an important growth factor receptor in hematopoiesis, and gain-of-function mutations of the receptor contribute to the transformation of acute myeloid leukemia (AML). The suppressors of cytokine signaling 6 (SOCS6) is a member of the SOCS family of E3 ubiquitin ligases that can regulate receptor tyrosine kinases signal transduction. In this study we analyzed the role of SOCS6 in Flt3 signal transduction. The results show that ligand stimulation to Flt3 can induce association of SOCS6 and Flt3 and tyrosine phosphorylation of SOCS6. Phospho-peptide fishing indicates that SOCS6 binds directly to phospho-tyrosine 591 and 919 of Flt3. By using stable transfected Ba/F3 cells with Flt3 and/or SOCS6, we show that the presence of SOCS6 can enhance ubiquitination of Flt3 as well as internalization and degradation of the receptor. The presence of SOCS6 also induces weaker activation of Erk1/2 but not Akt in transfected Ba/F3 and UT-7 cells, and in OCI-AML-5 cells. The absence of SOCS6 promotes Ba/F3 and UT-7 cell proliferation induced by oncogenic internal-tandem-duplications (ITDs) of Flt3. Taken together, these results suggest that SOCS6 negatively regulates Flt3 activation and downstream Erk signaling pathway and cell proliferation.
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| 16. |
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| 17. |
- Kazi, Julhash U., et al.
(författare)
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Tyrosine 842 in the activation loop is required for full transformation by the oncogenic mutant FLT3-ITD
- 2017
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Ingår i: Cellular and Molecular Life Sciences. - : Springer Science and Business Media LLC. - 1420-682X .- 1420-9071. ; 74:14, s. 2679-2688
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Tidskriftsartikel (refereegranskat)abstract
- The type III receptor tyrosine kinase FLT3 is frequently mutated in acute myeloid leukemia. Oncogenic FLT3 mutants display constitutive activity leading to aberrant cell proliferation and survival. Phosphorylation on several critical tyrosine residues is known to be essential for FLT3 signaling. Among these tyrosine residues, Y842 is located in the so-called activation loop. The position of this tyrosine residue is well conserved in all receptor tyrosine kinases. It has been reported that phosphorylation of the activation loop tyrosine is critical for catalytic activity for some but not all receptor tyrosine kinases. The role of Y842 residue in FLT3 signaling has not yet been studied. In this report, we show that Y842 is not important for FLT3 activation or ubiquitination but plays a critical role in regulating signaling downstream of the receptor as well as controlling receptor stability. We found that mutation of Y842 in the FLT3-ITD oncogenic mutant background reduced cell viability and increased apoptosis. Furthermore, the introduction of the Y842 mutation in the FLT3-ITD background led to a dramatic reduction in in vitro colony forming capacity. Additionally, mice injected with cells expressing FLT3-ITD/Y842F displayed a significant delay in tumor formation, compared to FLT3-ITD expressing cells. Microarray analysis comparing gene expression regulated by FLT3-ITD versus FLT3-ITD/Y842F demonstrated that mutation of Y842 causes suppression of anti-apoptotic genes. Furthermore, we showed that cells expressing FLT3-ITD/Y842F display impaired activity of the RAS/ERK pathway due to reduced interaction between FLT3 and SHP2 leading to reduced SHP2 activation. Thus, we suggest that Y842 is critical for FLT3-mediated RAS/ERK signaling and cellular transformation.
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| 18. |
- Ke, Hengning, et al.
(författare)
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Germline mutations of KIT in gastrointestinal stromal tumor (GIST) and mastocytosis
- 2016
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Ingår i: Cell and Bioscience. - : Springer Science and Business Media LLC. - 2045-3701. ; 6:1
-
Forskningsöversikt (refereegranskat)abstract
- Somatic mutations of KIT are frequently found in mastocytosis and gastrointestinal stromal tumor (GIST), while germline mutations of KIT are rare, and only found in few cases of familial GIST and mastocytosis. Although ligand-independent activation is the common feature of KIT mutations, the phenotypes mediated by various germline KIT mutations are different. Germline KIT mutations affect different tissues such as interstitial cells of Cajal (ICC), mast cells or melanocytes, and thereby lead to GIST, mastocytosis, or abnormal pigmentation. In this review, we summarize germline KIT mutations in familial mastocytosis and GIST and discuss the possible cellular context dependent transforming activity of KIT mutations.
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| 19. |
- Ke, Hengning, et al.
(författare)
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High expression of CD34 and α6-integrin contributes to the cancer-initiating cell behaviour in ultraviolet-induced mouse skin squamous cell carcinoma
- 2020
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Ingår i: Journal of Cancer. - : Ivyspring International Publisher. - 1837-9664. ; 11:23, s. 6760-6767
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Tidskriftsartikel (refereegranskat)abstract
- Squamous cell carcinoma caused by ultraviolet light exposure represents over 40% of all malignant diseases. It is one of the most commonly found human tumours. Tumour mass within squamous cell carcinoma consists of various cell types, including cancer-initiating cells that are responsible for tumour progression, metastasis and chemoresistance and implicated in clinical relapse. In the present study, we aimed to characterise whether the cell population with high CD34 and α6-integrin expression behave as cancer-initiating cells within ultraviolet-induced squamous cell carcinoma in mouse skin. CD34highα6-integrinhigh compared to CD34lowα6-integrinhigh cells isolated from ultraviolet-induced squamous cell carcinoma could propagate effectively by displaying greater tumour initiating and self-renewal abilities. Our study suggests that CD34highα6-integrinhigh cells act as initiators upon ultraviolet-induced skin squamous cell carcinoma.
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| 20. |
- Lennartsson, Johan, et al.
(författare)
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C-Kit signal transduction and involvement in cancer
- 2005
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Ingår i: Cancer Therapy. ; 3, s. 5-28
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Forskningsöversikt (refereegranskat)abstract
- Receptor tyrosine kinases, such as c-Kit, are proteins whose function it is to transduce signals from the environment into the cell leading to complex behaviors such as proliferation, migration, survival and differentiation. Many of these behaviors are deregulated in cancer, which is characterized by uncontrolled proliferation, insensitivity towards death stimuli, migration of tumor cells away from the primary tumor site and in some cases also block of cellular differentiation leaving the cell in an immature proliferative state. To be able to target these processes it is vital to have a detailed understanding of the receptor function and the downstream pathways activated. In this article we will review the mechanisms by which c-Kit induces signal transduction as well as describing tumors in which c-Kit function is perturbed.
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| 21. |
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| 22. |
- Liang, Jinping, et al.
(författare)
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Tuning the protein phosphorylation by receptor type protein tyrosine phosphatase epsilon (PTPRE) in normal and cancer cells
- 2019
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Ingår i: Journal of Cancer. - : Ivyspring International Publisher. - 1837-9664. ; 10:1, s. 105-111
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Tidskriftsartikel (refereegranskat)abstract
- Tyrosine phosphorylation is an important post-translation modification of proteins that is controlled by tyrosine kinases and phosphatases. Disruption of the balance between the activity of tyrosine kinases and phosphatases may result in diseases. Receptor type protein tyrosine phosphatase epsilon (PTPRE) is closely related with receptor type protein tyrosine phosphatase alpha (PTPRA). PTPRE has been studied in osteoclast cells, nerve cells, hematopoietic cells, cancer cells and others, and it has different functions among various tissues. In this review, we summarized the current knowledge about the regulation of PTPRE on cellular signal transduction and its function under normal and pathological conditions.
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| 23. |
- Lindblad, Oscar, et al.
(författare)
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BEX1 acts as a tumor suppressor in acute myeloid leukemia.
- 2015
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Ingår i: Oncotarget. - 1949-2553. ; 6:25, s. 21395-21405
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Tidskriftsartikel (refereegranskat)abstract
- Acute myeloid leukemia (AML) is a heterogeneous disease of the myeloid lineage. About 35% of AML patients carry an oncogenic FLT3 mutant making FLT3 an attractive target for treatment of AML. Major problems in the development of FLT3 inhibitors include lack of specificity, poor response and development of a resistant phenotype upon treatment. Further understanding of FLT3 signaling and discovery of novel regulators will therefore help to determine additional pharmacological targets in FLT3-driven AML. In this report, we identified BEX1 as a novel regulator of oncogenic FLT3-ITD-driven AML. We showed that BEX1 expression was down-regulated in a group of AML patients carrying FLT3-ITD. Loss of BEX1 expression resulted in poor overall survival (hazard ratio, HR = 2.242, p = 0.0011). Overexpression of BEX1 in mouse pro-B and myeloid cells resulted in decreased FLT3-ITD-dependent cell proliferation, colony and tumor formation, and in increased apoptosis in vitro and in vivo. BEX1 localized to the cytosolic compartment of cells and significantly decreased FLT3-ITD-induced AKT phosphorylation without affecting ERK1/2 or STAT5 phosphorylation. Our data suggest that the loss of BEX1 expression in FLT3-ITD driven AML potentiates oncogenic signaling and leads to decreased overall survival of the patients.
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| 24. |
- Lindblad, Oscar, et al.
(författare)
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PI3 kinase is indispensable for oncogenic transformation by the V560D mutant of c-Kit in a kinase-independent manner.
- 2015
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Ingår i: Cellular and Molecular Life Sciences. - : Springer Science and Business Media LLC. - 1420-9071 .- 1420-682X. ; 72:22, s. 4399-4407
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Tidskriftsartikel (refereegranskat)abstract
- Oncogenic mutants of c-Kit are often found in mastocytosis, gastrointestinal stromal tumors and acute myeloid leukemia. The activation mechanism of the most commonly occurring mutation, D816V in exon 17 of c-Kit, has been well-studied while other mutations remain fairly uncharacterized in this respect. In this study, we show that the constitutive activity of the exon 11 mutant V560D is weaker than the D816V mutant. Phosphorylation of downstream signaling proteins induced by the ligand for c-Kit, stem cell factor, was stronger in c-Kit/V560D expressing cells than in cells expressing c-kit/D816V. Although cells expressing c-Kit/V560D showed increased ligand-independent proliferation and survival compared to wild-type c-Kit-expressing cells, these biological effects were weaker than in c-Kit/D816V-expressing cells. In contrast to cells expressing wild-type c-Kit, cells expressing c-Kit/V560D were independent of Src family kinases for downstream signaling. However, the independence of Src family kinases was not due to a Src-like kinase activity that c-Kit/D816V displayed. Point mutations that selectively block the association of PI3 kinase with c-Kit/V560D inhibited ligand-independent activation of the receptor, while inhibition of the kinase activity of PI3 kinase with pharmacological inhibitors did not affect the kinase activity of the receptor. This suggests a lipid kinase-independent key role of PI3 kinase in c-Kit/V560D-mediated oncogenic signal transduction. Thus, PI3 kinase is an attractive therapeutic target in malignancies induced by c-Kit mutations independent of its lipid kinase activity.
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| 25. |
- Lindblad, Oscar, et al.
(författare)
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The role of HOXB2 and HOXB3 in acute myeloid leukemia.
- 2015
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Ingår i: Biochemical and Biophysical Research Communications. - : Elsevier BV. - 1090-2104 .- 0006-291X. ; 467:4, s. 742-747
-
Tidskriftsartikel (refereegranskat)abstract
- Acute myeloid leukemia (AML) is a heterogeneous aggressive disease and the most common form of adult leukemia. Mutations in the type III receptor tyrosine kinase FLT3 are found in more than 30% of patients. Drugs against FLT3 have been developed for the treatment of AML, but they lack specificity, show poor response and lead to the development of a resistant phenotype upon treatment. Therefore, a deeper understanding of FLT3 signaling will facilitate identification of additional pharmacological targets in FLT3-driven AML. In this report, we identify HOXB2 and HOXB3 as novel regulators of oncogenic FLT3-ITD-driven AML. We show that HOXB2 and HOXB3 expression is upregulated in a group of AML patients carrying FLT3-ITD. Overexpression of HOXB2 or HOXB3 in mouse pro-B cells resulted in decreased FLT3-ITD-dependent cell proliferation as well as decreased colony formation and increased apoptosis. Expression of HOXB2 or HOXB3 resulted in a significant decrease in FLT3-ITD-induced AKT, ERK, p38 and STAT5 phosphorylation. Our data suggest that HOXB2 and HOXB3 act as a tumor suppressors in FLT3-ITD driven AML.
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| 26. |
- Liu, Anbu, et al.
(författare)
-
DDR1/2 enhance KIT activation and imatinib resistance of primary and secondary KIT mutants in gastrointestinal stromal tumors
- 2024
-
Ingår i: Molecular Carcinogenesis. - 0899-1987. ; 63:1, s. 75-93
-
Tidskriftsartikel (refereegranskat)abstract
- Gastrointestinal stromal tumors (GISTs) are predominantly initiated by KIT mutations. In this study, we observed that discoidin domain receptors 1 and 2 (DDR1 and DDR2) exhibited high expression in GISTs, were associated with KIT, and enhanced the activation of both wild-type KIT and primary KIT mutants. Inhibition of DDR1/2 led to a reduction in the activation of KIT and its downstream signaling molecules, ultimately impairing GIST cell survival and proliferation in vitro. Consequently, treatment of mice carrying germline KIT/V558A mutation with DDR1/2 inhibitor significantly impeded tumor growth, and the combined use of DDR1/2 inhibitor and imatinib, the first-line targeted therapeutic agent for GISTs, markedly enhanced tumor growth suppression. In addition, DDR1/2 inhibition resulted in decreased KIT expression, while KIT inhibition led to upregulation of DDR1/2 expression in GISTs. The presence of DDR1/2 also decreased the sensitivity of wild-type KIT or primary KIT mutants to imatinib, indicating a possible role for DDR1/2 in promoting GIST survival during KIT-targeted therapy. The development of drug-resistant secondary KIT mutations is a primary factor contributing to GIST recurrence following targeted therapy. Similar to primary KIT mutants, DDR1/2 can associate with and enhance the activation of secondary KIT mutants, further diminishing their sensitivity to imatinib. In summary, our data demonstrate that DDR1/2 contribute to KIT activation in GISTs and strengthen resistance to imatinib for both primary and secondary KIT mutants, providing a rationale for further exploration of DDR1/2 targeting in GIST treatment.
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| 27. |
- Ma, Lijun, et al.
(författare)
-
Grainyhead-like 2 in development and cancer
- 2017
-
Ingår i: Tumor Biology. - : IOS Press. - 1010-4283 .- 1423-0380. ; 39:5
-
Forskningsöversikt (refereegranskat)abstract
- Grainyhead-like 2 is a human homolog of Drosophila grainyhead. It inhibits epithelial-to-mesenchymal transition that is necessary for cell migration, and it is involved in neural tube closure, epithelial morphogenesis, and barrier formation during embryogenesis by regulation of the expression of cell junction proteins such as E-cadherin and vimentin. Cancer shares many common characters with development such as epithelial-to-mesenchymal transition. In addition to its important role in development, grainyhead-like 2 is implicated in carcinogenesis as well. However, the reports on grainyhead-like 2 in various cancers are controversial. Grainyhead-like 2 can act as either a tumor suppressor or an oncogene with the mechanisms not well elucidated. In this review, we summarized recent progress on grainyhead-like 2 in development and cancer in order to get an insight into the regulation network of grainyhead-like 2 and understand the roles of grainyhead-like 2 in various cancers.
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| 28. |
- Masson, Kristina, et al.
(författare)
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A role of Gab2 association in Flt3 ITD mediated Stat5 phosphorylation and cell survival.
- 2009
-
Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 146, s. 193-202
-
Tidskriftsartikel (refereegranskat)abstract
- Summary The haematopoietic growth factor receptor Flt3 has been implicated as major cause of transformation in acute myeloid leukaemia. Intracellular signals mediated by wild-type Flt3 are involved in cell differentiation and survival whereas signalling via the mutant Flt3 ITD (internal tandem duplication) promotes enhanced cell growth. In this study, we identified tyrosines 768, 955 and 969 of Flt3 as phosphorylation sites and mediators of growth factor receptor binding protein 2 (Grb2) interaction, leading to the association of Grb2 associated binder 2 (Gab2) and contributing to proliferation and survival. Ba/F3 cells were transfected with either the wild-type Flt3 or the ITD, with or without a triple mutation of the Grb2 binding sites, and characterised in terms of proliferation and viability. Interestingly, the Flt3 ITD promoted increased survival but after introducing the triple mutation, this phenotype was lost. When looking into different downstream pathways, this effect was mainly caused by decreased phosphoinositide 3-kinase and Stat5 signalling, and the Flt3 ITD carrying the Grb2 binding mutations showed less Akt and Stat5 activation compared to the regular Flt3 ITD receptor. These findings not only reveal novel phosphorylation sites in Flt3 but contribute to the understanding of the molecular mechanism by which Flt3 ITD functions in pathological conditions.
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| 29. |
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| 30. |
- Moharram, Sausan A, et al.
(författare)
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Src-like adaptor protein 2 (SLAP2) binds to and inhibits FLT3 signaling
- 2016
-
Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; , s. 1-13
-
Tidskriftsartikel (refereegranskat)abstract
- Fms-like tyrosine kinase (FLT3) is a frequently mutated oncogene in acute myeloid leukemia (AML). FLT3 inhibitors display promising results in a clinical setting, but patients relapse after short-term treatment due to the development of resistant disease. Therefore, a better understanding of FLT3 downstream signal transduction pathways will help to identify an alternative target for the treatment of AML patients carrying oncogenic FLT3. Activation of FLT3 results in phosphorylation of FLT3 on several tyrosine residues that recruit SH2 domain-containing signaling proteins. We screened a panel of SH2 domain-containing proteins and identified SLAP2 as a potent interacting partner of FLT3. We demonstrated that interaction occurs when FLT3 is activated, and also, an intact SH2 domain of SLAP2 is required for binding. SLAP2 binding sites in FLT3 mainly overlap with those of SRC. SLAP2 over expression in murine proB cells or myeloid cells inhibited oncogenic FLT3-ITD-mediated cell proliferation and colony formation in vitro, and tumor formation in vivo. Microarray analysis suggests that higher SLAP2 expression correlates with a gene signature similar to that of loss of oncogene function. Furthermore, FLT3-ITD positive AML patients with higher SLAP2 expression displayed better prognosis compared to those with lower expression of SLAP2. Expression of SLAP2 blocked FLT3 downstream signaling cascades including AKT, ERK, p38 and STAT5. Finally, SLAP2 accelerated FLT3 degradation through enhanced ubiquitination. Collectively, our data suggest that SLAP2 acts as a negative regulator of FLT3 signaling and therefore, modulation of SLAP2 expression levels may provide an alternative therapeutic approach for FLT3-ITD positive AML.
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| 31. |
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| 32. |
- Pedersen, Malin, et al.
(författare)
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Stem cell factor induces HIF-1alpha at normoxia in hematopoietic cells.
- 2008
-
Ingår i: Biochemical and Biophysical Research Communications. - : Elsevier BV. - 1090-2104 .- 0006-291X. ; 98:103, s. 98-103
-
Tidskriftsartikel (refereegranskat)abstract
- Signaling by the receptor for stem cell factor (SCF), c-Kit, is of major importance for hematopoiesis, melanogenesis and reproduction, and the biological responses are commonly proliferation and cell survival. Thus, constitutive activation due to c-Kit mutations is involved in the pathogenesis of several forms of cancer, e.g. leukemias, gastrointestinal stromal tumors and testicular tumors. Tumor survival requires oxygen supply through induced neovascularization, a process largely mediated by the vascular endothelial growth factor (VEGF), a prominent target of the transcription factors hypoxia-inducible factor-1 (HIF-1) and HIF-2. Using Affymetrix microarrays we have identified genes that are upregulated following SCF stimulation. Interestingly, many of the genes induced were found to be related to a hypoxic response. These findings were corroborated by our observation that SCF stimulation of the hematopoietic cell lines M-07e induces HIF-1alpha and HIF-2alpha protein accumulation at normoxia. In addition, SCF-induced HIF-1alpha was transcriptionally active, and transcribed HIF-1 target genes such as VEGF, BNIP3, GLUT1 and DEC1, an effect that could be reversed by siRNA against HIF-1alpha. We also show that SCF-induced accumulation of HIF-1alpha is dependent on both the PI-3-kinase and Ras/MEK/Erk pathways. Our data suggest a novel mechanism of SCF/c-Kit signaling in angiogenesis and tumor progression.
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| 33. |
- Pedersen, Malin, et al.
(författare)
-
The c-Kit/D816V mutation eliminates the differences in signal transduction and biological responses between two isoforms of c-Kit.
- 2009
-
Ingår i: Cellular Signalling. - : Elsevier BV. - 1873-3913 .- 0898-6568. ; 21, s. 413-418
-
Tidskriftsartikel (refereegranskat)abstract
- Activating mutations of codon 816 of the Kit gene have been implicated in malignant cell growth of acute myeloid leukemia (AML), systemic mastocytosis and germ cell tumors. Substitution of aspartic acid with valine (D816V) renders the receptor independent of ligand for activation and signaling. Wild-type c-Kit is a tyrosine kinase receptor that requires its ligand, stem cell factor (SCF), for activation. Several isoforms of c-Kit exist as a result of alternative mRNA splicing, of which two are characterized by the presence or absence of four amino acids (GNNK- and GNNK+, respectively) in the extracellular domain. The two isoforms show differences in signal transduction and biological activities and the shorter isoform seems to be highly expressed than the longer isoform in human malignancies. In this study we analysed the signal transduction downstream of the oncogenic c-Kit mutant D816V in an isoform specific context, using the hematopoietic cell line Ba/F3 stably transfected with the different versions of isoform and mutant receptor. Our data show that in contrast to the differences shown in the activation of wild-type c-Kit isoforms, both isoforms of c-Kit/D816V are constitutively phosphorylated to the same extent. By the use of Western blot analysis we investigated the activation of different signaling proteins and found that both D816V/GNNK- and D816V/GNNK+ constitutively phosphorylated Gab2, Shc, SHP-2 and Cbl to almost the same extent as c-Kit/GNNK-. In addition, both isoforms of c-Kit/D816V induced SCF-independent cell survival and proliferation equally well. This is in contrast to wild-type c-Kit, where c-Kit/GNNK- induced better cell survival and stronger proliferation than c-Kit/GNNK+, and both required stimulation with SCF. Taken together, these findings reveal that the differences in downstream signal transduction and biological responses between the two GNNK isoforms are eliminated by the D816V mutant.
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| 34. |
- Phung, Bengt, et al.
(författare)
-
C-KIT Signaling Depends on Microphthalmia-Associated Transcription Factor for Effects on Cell Proliferation.
- 2011
-
Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:8
-
Tidskriftsartikel (refereegranskat)abstract
- The development of melanocytes is regulated by the tyrosine kinase receptor c-KIT and the basic-helix-loop-helix-leucine zipper transcription factor Mitf. These essential melanocyte survival regulators are also well known oncogenic factors in malignant melanoma. Despite their importance, not much is known about the regulatory mechanisms and signaling pathways involved. In this study, we therefore sought to identify the signaling pathways and mechanisms involved in c-KIT mediated regulation of Mitf. We report that c-KIT stimulation leads to the activation of Mitf specifically through the c-KIT phosphorylation sites Y721 (PI3 kinase binding site), Y568 and Y570 (Src binding site). Our study not only confirms the involvement of Ras-Erk signaling pathway in the activation of Mitf, but also establishes that Src kinase binding to Y568 and Y570 of c-KIT is required. Using specific inhibitors we observe and verify that c-KIT induced activation of Mitf is dependent on PI3-, Akt-, Src-, p38- or Mek kinases. Moreover, the proliferative effect of c-KIT is dependent on Mitf in HEK293T cells. In contrast, c-KIT Y568F and Y721F mutants are less effective in driving cell proliferation, compared to wild type c-KIT. Our results reveal novel mechanisms by which c-KIT signaling regulates Mitf, with implications for understanding both melanocyte development and melanoma.
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| 35. |
- Phung, Bengt, et al.
(författare)
-
KITD816V induces SRC-mediated tyrosine phosphorylation of MITF and altered transcription program in melanoma
- 2017
-
Ingår i: Molecular Cancer Research. - 1541-7786. ; 15:9, s. 1265-1274
-
Tidskriftsartikel (refereegranskat)abstract
- The oncogenic D816V mutation of the KIT receptor is well characterized in systemic mastocytosis and acute myeloid leukemia. Although KITD816V has been found in melanoma, its function and involvement in this malignancy is not understood. Here we show that KITD816V induces tyrosine phosphorylation of MITF through a triple protein complex formation between KIT, MITF, and SRC family kinases. In turn, phosphorylated MITF activates target genes that are involved in melanoma proliferation, cellcycle progression, suppression of senescence, survival, and invasion. By blocking the triple protein complex formation, thus preventing MITF phosphorylation, the cells became hypersensitive to SRC inhibitors. We have therefore delineated a mechanism behind the oncogenic effects of KITD816V in melanoma and provided a rationale for the heightened SRC inhibitor sensitivity in KITD816V transformed cells. Implications: This study demonstrates that an oncogenic tyrosine kinase mutant, KITD816V, can alter the transcriptional program of the transcription factor MITF in melanoma.
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| 36. |
- Razumovskaya, Elena, et al.
(författare)
-
Inhibition of MEK5 by BIX02188 induces apoptosis in cells expressing the oncogenic mutant FLT3-ITD.
- 2011
-
Ingår i: Biochemical and Biophysical Research Communications. - : Elsevier BV. - 1090-2104 .- 0006-291X. ; 412:2, s. 307-312
-
Tidskriftsartikel (refereegranskat)abstract
- Fms-like tyrosine kinase-3 (FLT3) is a growth factor receptor normally expressed on hematopoietic progenitor cells. Approximately one third of all patients with AML carry an activating mutation in FLT3 that drives proliferation and survival of the leukemic cells. The most common activating mutation is the so-called internal tandem duplication (ITD), which involves an in-frame duplication of a segment of varying length in the region of the FLT3 gene that encodes the juxtamembrane domain. The pathways downstream of FLT3-ITD are partially known but further knowledge regarding the downstream signal transduction molecules is important in order to develop alternative strategies for pharmacological intervention. In this paper we have studied the role of MEK/ERK5 in FLT3-ITD mediated transformation. We have found that both wild-type FLT3 and FLT3-ITD activate MEK5 leading to the activation of ERK5. By use of the selective inhibitor of MEK5, BIX02188, we have shown that activation of AKT downstream of FLT3 is partially dependent on ERK5. Furthermore, inhibition of MEK5/ERK5 induces apoptosis of both FLT3-ITD transfected Ba/F3 cells as well as the FLT3-ITD carrying leukemic cell lines MV4-11 and MOLM-13. These results suggest that MEK5/ERK5 is important for FLT3-ITD induced hematopoietic transformation and may thus represent an alternative therapeutic target in the treatment of FLT3-ITD positive leukemia.
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| 37. |
- Reinbothe, Susann, et al.
(författare)
-
EPO-independent functional EPO receptor in breast cancer enhances estrogen receptor activity and promotes cell proliferation.
- 2014
-
Ingår i: Biochemical and Biophysical Research Communications. - : Elsevier BV. - 1090-2104 .- 0006-291X. ; 445:1, s. 163-169
-
Tidskriftsartikel (refereegranskat)abstract
- The main function of Erythropoietin (EPO) and its receptor (EPOR) is the stimulation of erythropoiesis. Recombinant human EPO (rhEPO) is therefore used to treat anemia in cancer patients. However, clinical trials have indicated that rhEPO treatment might promote tumor progression and has a negative effect on patient survival. In addition, EPOR expression has been detected in several cancer forms. Using a newly produced anti-EPOR antibody that reliably detects the full-length isoform of the EPOR we show that breast cancer tissue and cells express the EPOR protein. rhEPO stimulation of cultured EPOR expressing breast cancer cells did not result in increased proliferation, overt activation of EPOR (receptor phosphorylation) or a consistent activation of canonical EPOR signaling pathway mediators such as JAK2, STAT3, STAT5, or AKT. However, EPOR knockdown experiments suggested functional EPO receptors in estrogen receptor positive (ERα(+)) breast cancer cells, as reduced EPOR expression resulted in decreased proliferation. This effect on proliferation was not seen in ERα negative cells. EPOR knockdown decreased ERα activity further supports a mechanism by which EPOR affects proliferation via ERα-mediated mechanisms. We show that EPOR protein is expressed in breast cancer cells, where it appears to promote proliferation by an EPO-independent mechanism in ERα expressing breast cancer cells.
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| 38. |
- Shah, Kinjal, et al.
(författare)
-
T cell receptor (TCR) signaling in health and disease
- 2021
-
Ingår i: Signal Transduction and Targeted Therapy. - : Springer Science and Business Media LLC. - 2059-3635. ; 6:1
-
Forskningsöversikt (refereegranskat)abstract
- Interaction of the T cell receptor (TCR) with an MHC-antigenic peptide complex results in changes at the molecular and cellular levels in T cells. The outside environmental cues are translated into various signal transduction pathways within the cell, which mediate the activation of various genes with the help of specific transcription factors. These signaling networks propagate with the help of various effector enzymes, such as kinases, phosphatases, and phospholipases. Integration of these disparate signal transduction pathways is done with the help of adaptor proteins that are non-enzymatic in function and that serve as a scaffold for various protein–protein interactions. This process aids in connecting the proximal to distal signaling pathways, thereby contributing to the full activation of T cells. This review provides a comprehensive snapshot of the various molecules involved in regulating T cell receptor signaling, covering both enzymes and adaptors, and will discuss their role in human disease.
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| 39. |
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| 40. |
- Sun, Jianmin, et al.
(författare)
-
GAB2 is involved in differential pi3-kinase signaling by two splice forms of C-kit.
- 2008
-
Ingår i: Journal of Biological Chemistry. - 1083-351X. ; 283:41, s. 27444-27451
-
Tidskriftsartikel (refereegranskat)abstract
- The stem cell factor receptor/c-Kit plays an important physiological role in hematopoesis, melanogenesis and gametogenesis. It has also been implicated in numerous human malignancies. Signal transduction pathways shown to be of importance for c-Kit mediated transformation include the PI3-kinase/Akt pathway. We have previously shown that two alternative splice forms of c-Kit, denoted GNNK- and GNNK+ respectively, mediate distinctively different signals. In this study we find that in the hematopoietic cell line Ba/F3, the GNNK- c-Kit mediates a substantially stronger activation of PI3-kinase/Akt than the GNNK+ c-Kit. This difference in signaling was shown to be dependent on the association of the scaffolding protein Gab2 to c-Kit and Src-mediated phosphorylation of Gab2, to be independent of the direct association of PI3-kinase with c-Kit. Furthermore, proliferation and survival of Ba/F3 cells expressing a mutant of c-Kit that fails to bind to PI3-kinase directly was slightly decreased compared to wild-type c-Kit expressing cells. Using siRNA technology we further verified a role of Gab2 in inducing activation of PI3-kinase/Akt downstream of c-Kit. To summarize, we show that PI3-kinase activation by c-Kit is both splice form dependent and cell type specific. Furthermore, activation of PI3-kinase by c-Kit is dependent both on the direct PI3-kinase binding site in c-Kit as well as on the phosphorylation of Gab2. The fact that c-Kit has been found mutated in numerous human malignancies including acute myeloid leukemia and that Gab2 often is overexpressed in acute myeloid leukemia suggests a potential role of Gab2 mediated PI3-kinase activation in transformation.
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| 41. |
- Sun, Jianmin, et al.
(författare)
-
Grb2 mediates negative regulation of stem cell factor receptor/c-Kit signaling by recruitment of Cbl.
- 2007
-
Ingår i: Experimental Cell Research. - : Elsevier BV. - 1090-2422 .- 0014-4827. ; 313:18, s. 3935-3942
-
Tidskriftsartikel (refereegranskat)abstract
- Aberrant activation of c-Kit is involved in a number of human diseases including cancers and leukemias. Certain receptor tyrosine kinases, such as epidermal growth factor receptor, have been shown to indirectly recruit Cbl through the adapter protein Grb2, leading to receptor ubiquitination and degradation. In order to study the role of Grb2 in c-Kit degradation, a series of mutations of the Grb2 binding sites in c-Kit were generated (Y703F, Y936F, and Y703F/Y936F). Since other signal transduction molecules are also known to bind Y703 and Y936, the more selective asparagine-to-alanine (N-to-A) mutants N705A, N938A, and N705A/N938A were generated. We could clearly demonstrate that binding of Grb2 was dependent on intact phosphorylation sites Y703 and Y936. Furthermore, we could demonstrate the presence of Cbl in a complex with Grb2 and c-Kit. Thus, Grb2 is able to indirectly recruit Cbl to c-Kit. In the N-to-A mutants, Cbl phosphorylation was strongly reduced, which correlated with reduced ubiquitination of c-Kit as well as decreased internalization and degradation of the receptor. Taken together, we have demonstrated that, in addition to its role in positive signaling via the Ras/Erk pathway, Grb2 mediates c-Kit degradation through recruitment of Cbl to c-Kit, leading to ubiquitination of c-Kit followed by internalization and degradation.
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| 42. |
- Sun, Jianmin, et al.
(författare)
-
Mesenchymal – Development and Regeneration Potential.
- 2015. - 2nd Edition
-
Ingår i: The SAGE Encyclopedia of Stem Cell Research. - 2455 Teller Road, Thousand Oaks California 91320 : SAGE Publications, Inc. - 9781483347684 - 9781483347660 ; , s. 752-755
-
Bokkapitel (refereegranskat)
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| 43. |
- Sun, Jianmin, et al.
(författare)
-
Mesenchymal Stem Cells
- 2015. - 2nd Edition
-
Ingår i: The SAGE Encyclopedia of Stem Cell Research. - 2455 Teller Road, Thousand Oaks California 91320 : SAGE Publications, Inc. - 9781483347684 - 9781483347660 ; , s. 762-764
-
Bokkapitel (övrigt vetenskapligt/konstnärligt)
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| 44. |
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| 45. |
- Sun, Jianmin, et al.
(författare)
-
The D816V mutation of c-Kit circumvents a requirement for Src family kinases in c-Kit signal transduction.
- 2009
-
Ingår i: Journal of Biological Chemistry. - 1083-351X. ; 284:17, s. 11039-11047
-
Tidskriftsartikel (refereegranskat)abstract
- The receptor tyrosine kinase c-Kit plays a critical role in hematopoiesis and gain-of-function mutations of the receptor are frequently seen in several malignancies, including acute myeloid leukemia (AML), gastrointestinal stromal tumors and testicular carcinoma. The most common mutation of c-Kit in these disorders is a substitution of the aspartic acid residue in position 816 to a valine (D816V), leading to constitutive activation of the receptor. In this study we aimed to investigate the role of Src family kinases in c-Kit/D816V signaling. Src family kinases are necessary for the phosphorylation of wild-type c-Kit as well as of activation of downstream signaling pathways including receptor ubiquitination and the Ras/Mek/Erk pathway. Our data demonstrate that, unlike wild-type c-Kit, the phosphorylation of c-Kit/D816V is not dependent on Src family kinases. In addition we found that neither receptor ubiquitination nor Erk activation by c-Kit/D816V required activation of Src family kinases. In vitro kinase assay using synthetic peptides revealed that c-Kit/D816V had an altered substrate specificity resembling Src and Abl tyrosine kinases. We further present evidence that, in contrast to wild-type c-Kit, Src family kinases are dispensable for c-Kit/D816V cell survival, proliferation and colony formation. Taken together, we demonstrate that the signal transduction pathways mediated by c-Kit/D816V are markedly different from those activated by wild-type c-Kit and that altered substrate specificity of c-Kit circumvents a need for Src family kinases in signaling of growth and survival, thereby contributing to the transforming potential of c-Kit/D816V.
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| 46. |
- Sun, Jianmin, et al.
(författare)
-
The PI3-kinase isoform p110 delta is essential for cell transformation induced by the D816V mutant of c-Kit in a lipid-kinase-independent manner
- 2014
-
Ingår i: Oncogene. - : Springer Science and Business Media LLC. - 0950-9232 .- 1476-5594. ; 33:46, s. 5360-5369
-
Tidskriftsartikel (refereegranskat)abstract
- PI3-kinase has a crucial role in transformation mediated by the oncogenic c-Kit mutant D816V. In this study, we demonstrate that the c-Kit/D816V-mediated cell survival is dependent on an intact direct binding of PI3-kinase to c-Kit. However, mutation of this binding site had little effect on the PI3-kinase activity in the cells, suggesting that c-Kit/D816V-mediated cell survival is dependent on PI3-kinase but not its kinase activity. Furthermore, inhibition of the lipid kinase activity of PI3-kinase led only to a slight inhibition of cell survival. Knockdown of the predominant PI3-kinase isoform p110 delta in c-Kit/D816V-expressing Ba/F3 cells led to reduced cell transformation both in vitro and in vivo without affecting the overall PI3-kinase activity. This suggests that p110 delta has a lipid-kinaseindependent role in c-Kit/D816V-mediated cell transformation. We furthermore demonstrate that p110 delta is phosphorylated at residues Y524 and S1039 and that phosphorylation requires an intact binding site for PI3-kinase in c-Kit/D816V. Overexpression of p110 delta carrying the Y523F and S1038A mutations significantly reduced c-Kit/D816V-mediated cell survival and proliferation. Taken together, our results demonstrate an important lipid-kinase-independent role of p110 delta in c-Kit/D816V-mediated cell transformation. This furthermore suggests that p110 delta could be a potential diagnostic factor and selective therapeutic target for c-Kit/D816V-expressing malignancies.
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| 47. |
- Sun, Jianmin, et al.
(författare)
-
XK-related protein 5 (XKR5) is a novel negative regulator of KIT/D816V-mediated transformation
- 2018
-
Ingår i: Oncogenesis. - : Springer Science and Business Media LLC. - 2157-9024. ; 7:6
-
Tidskriftsartikel (refereegranskat)abstract
- In order to investigate the molecular mechanisms by which the oncogenic mutant KIT/D816V causes transformation of cells, we investigated proteins that selectively bind KIT/D816V, but not wild-type KIT, as potential mediators of transformation. By mass spectrometry several proteins were identified, among them a previously uncharacterized protein denoted XKR5 (XK-related protein 5), which is related to the X Kell blood group proteins. We could demonstrate that interaction between XKR5 and KIT/D816V leads to phosphorylation of XKR5 at Tyr 369, Tyr487, and Tyr 543. Tyrosine phosphorylated XKR5 acts as a negative regulator of KIT signaling, which leads to downregulation of phosphorylation of ERK, AKT, and p38. This led to reduced proliferation and colony forming capacity in semi-solid medium. Taken together, our data demonstrate that XKR5 is a novel type of negative regulator of KIT-mediated transformation.
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| 48. |
- Sun, Mengtao, et al.
(författare)
-
Direct visual evidence for the chemical mechanism of surface-enhanced resonance Raman scattering via charge transfer: (II) Binding-site and quantum-size effects
- 2009
-
Ingår i: Journal of Raman Spectroscopy. - : Wiley. - 1097-4555 .- 0377-0486. ; 40:9, s. 1172-1177
-
Tidskriftsartikel (refereegranskat)abstract
- We describe quantum-size and binding-site effects on the chemical and local field enhancement mechanisms of surface-enhanced resonance Raman scattering (SERRS), in which the pyridine molecule is adsorbed on one of the vertices of the Ag-20 tetrahedron. We first investigated the influence of the binding site on normal Raman scattering (NRS) and excited state properties of optical absorption spectroscopy. Second, we investigated the quantum-size effect on the electromagnetic (EM) and chemical mechanism from 300 to 1000 nm with charge difference density. It is found that the strong absorption at around 350 nm is mainly the charge transfer (CT) excitation (CT between the molecule and the silver cluster) for large clusters, which is the direct evidence for the chemical enhancement mechanism for SERRS; for a small cluster the strong absorption around 350 nm is mainly intracluster excitation, which is the direct evidence for the EM enhancement mechanism. This conclusion is further confirmed with the general Mie theory. The plasmon peak in EM enhancement will be red-shifted with the increase of cluster size. The influence of the binding site and quantum-size effects on NRS, as well as chemical and EM enhancement mechanisms on SERRS, is significant. Copyright (C) 2009 John Wiley & Sons, Ltd.
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| 49. |
- Xiong, Jiantuan, et al.
(författare)
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Hypermethylation of endoplasmic reticulum disulfide oxidase 1α leads to trophoblast cell apoptosis through endoplasmic reticulum stress in preeclampsia
- 2018
-
Ingår i: Journal of Cellular Biochemistry. - : Wiley. - 0730-2312 .- 1097-4644. ; 119:10, s. 8588-8599
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Tidskriftsartikel (refereegranskat)abstract
- Abnormal trophoblast cell apoptosis is implicated in the pathogenesis of pregnancy-related disorders including preeclampsia (PE), and endoplasmic reticulum (ER) stress has been considered as a novel pathway in the regulation of cell apoptosis. In this study, we observed that both apoptosis and ER stress are triggered in trophoblast cells under hypoxia as well as in the placenta of PE rats. Quantitative polymerase chain reaction and Western blot analysis showed that the expression of endoplasmic reticulum disulfide oxidase 1α (ERO1α) is suppressed in trophoblast cells under hypoxia due to the hypermethylation of the ERO1α promoter region, and the inhibition of ERO1α expression plays an important role in ER stress and trophoblast cell apoptosis. Furthermore, we found that DNA methyltransferase 1 (DNMT1) is a key methyltransferase for DNA methylation in the regulation of ERO1α expression, and the binding level of DNMT1 to the ERO1α promoter is markedly elevated under hypoxia although DNMT1 expression is inhibited by hypoxia, suggesting that the binding level of DNMT1 to the ERO1α promoter region rather than the DNMT1 expression level contributes to the hypermethylation of ERO1α. Taken together, these results demonstrate that the hypermethylation of ERO1α mediated by increased binding of DNMT1 to the ERO1α promoter leads to trophoblast cell apoptosis through ER stress in the placenta of PE rats, which shed insight into the etiology of PE and might present a validated therapeutic target for the treatment of PE.
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- Yuan, Bin, et al.
(författare)
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Dose-effect relationship of apoptosis induced by fission-neutron in murine thymocytes
- 2000
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Ingår i: Chinese Journal of Radiological Medical Protection. ; 20, s. 87-87
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Tidskriftsartikel (refereegranskat)abstract
- Objective To investigate the effectiveness of high LET fission-neutron to induce apoptosis in murine thymocytes and to compare it with that of low LET 60Co γ-ray. Methods Apoptosis induction was studied qualitatively by light and transmission electron microscopy and DNA gel electrophoresis,also quantitatively by flow cytometry(FCM) and diphenylamine (DPA)methods. Results DNA ladders of murine thymocytes were detectable,the typical apoptosis of thymocytes could be observed morphologically by means of light and electron microscopy at 6 h after fission-neutron irradiation with doses ranging from 0.5 to 5.0 Gy,meanwhile the percentages of apoptosis increased with increasing doses.After exposure to γ-rays with doses ranging from 1.0 to 30 Gy,the expermiental results were similar to those from neutron radiation.The incidence of apoptosis peaked at about 20 Gy，the percentages did not increase further when doses increased. Conclusion Apoptosis of murine thymocytes can be induced when mice are exposed to either fission-neutron (0.5-5.0 Gy) or to γ-ray (1-30 Gy).Although the relationship between apoptosis and radiation doses is similar,the percentage of apoptosis induced by neutron irradiation is higher than that induced by γ-irradiation.The RBE values of fission-neutron for inducing apoptosis murine thymocytes are 2.09 (by FCM method) and 2.37 (by DPA method),respectively.These results also suggest that fission-neutron-induced murine immune tissue is more severe than that induced by γ-rays at several hours post-irradiation and this might be the basis for heavy damage to immune tissues induced by fission-neutron-irradiation in later period.
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