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Träfflista för sökning "WFRF:(Påhlman Lars) ;pers:(Påhlman Sven)"

Sökning: WFRF:(Påhlman Lars) > Påhlman Sven

  • Resultat 1-9 av 9
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1.
  • Agarwal, Shruti, et al. (författare)
  • The activation loop tyrosine 823 is essential for the transforming capacity of the c-Kit oncogenic mutant D816V.
  • 2015
  • Ingår i: Oncogene. - : Springer Science and Business Media LLC. - 1476-5594 .- 0950-9232. ; 34:35, s. 4581-4590
  • Tidskriftsartikel (refereegranskat)abstract
    • Oncogenic c-Kit mutations have been shown to display ligand-independent receptor activation and cell proliferation. A substitution of aspartate to valine at amino acid 816 (D816V) is one of the most commonly found oncogenic c-Kit mutations and is found in >90% of cases of mastocytosis and less commonly in germ-cell tumors, core-binding factor acute myeloid leukemia and mucosal melanomas. The mechanisms by which this mutation leads to constitutive activation and transformation are not fully understood. Previous studies have shown that the D816V mutation causes a structural change in the activation loop (A-loop), resulting in weaker binding of the A-loop to the juxtamembrane domain. In this paper, we have investigated the role of Y823, the only tyrosine residue in the A-loop, and its role in oncogenic transformation by c-Kit/D816V by introducing the Y823F mutation. Although dispensable for the kinase activity of c-Kit/D816V, the presence of Y823 was crucial for cell proliferation and survival. Furthermore, mutation of Y823 selectively downregulates the Ras/Erk and Akt pathways as well as the phosphorylation of STAT5 and reduces the transforming capacity of the D816V/c-Kit in vitro. We further show that mice injected with cells expressing c-Kit/D816V/Y823F display significantly reduced tumor size as well as tumor weight compared with controls. Finally, microarray analysis, comparing Y823F/D816V cells with cells expressing c-Kit/D816V, demonstrate that mutation of Y823 causes upregulation of proapoptotic genes, whereas genes of survival pathways are downregulated. Thus, phosphorylation of Y823 is not necessary for kinase activation, but essential for the transforming ability of the c-Kit/D816V mutant.Oncogene advance online publication, 1 December 2014; doi:10.1038/onc.2014.383.
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2.
  • Alam, Muhammad Wasi, et al. (författare)
  • HIF2α contributes to antiestrogen resistance via positive bilateral crosstalk with EGFR in breast cancer cells.
  • 2016
  • Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 7:10, s. 50-11238
  • Tidskriftsartikel (refereegranskat)abstract
    • The majority of breast cancers express estrogen receptor α (ERα), and most patients with ERα-positive breast cancer benefit from antiestrogen therapy. The ERα-modulator tamoxifen and ERα-downregulator fulvestrant are commonly employed antiestrogens. Antiestrogen resistance remains a clinical challenge, with few effective treatments available for patients with antiestrogen-resistant breast cancer. Hypoxia, which is intrinsic to most tumors, promotes aggressive disease, with the hypoxia-inducible transcription factors HIF1 and HIF2 regulating cellular responses to hypoxia. Here, we show that the ERα-expressing breast cancer cells MCF-7, CAMA-1, and T47D are less sensitive to antiestrogens when hypoxic. Furthermore, protein and mRNA levels of HIF2α/HIF2A were increased in a panel of antiestrogen-resistant cells, and antiestrogen-exposure further increased HIF2α expression. Ectopic expression of HIF2α in MCF-7 cells significantly decreased sensitivity to antiestrogens, further implicating HIF2α in antiestrogen resistance. EGFR is known to contribute to antiestrogen resistance: we further show that HIF2α drives hypoxic induction of EGFR and that EGFR induces HIF2α expression. Downregulation or inhibition of EGFR led to decreased HIF2α levels. This positive and bilateral HIF2-EGFR regulatory crosstalk promotes antiestrogen resistance and, where intrinsic hypoxic resistance exists, therapy itself may exacerbate the problem. Finally, inhibition of HIFs by FM19G11 restores antiestrogen sensitivity in resistant cells. Targeting HIF2 may be useful for counteracting antiestrogen resistance in the clinic.
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3.
  • Cetinkaya, Cihan, et al. (författare)
  • Combined IFN-gamma and retinoic acid treatment targets the N-Myc/Max/Mad1 network resulting in repression of N-Myc target genes in MYCN-amplified neuroblastoma cells
  • 2007
  • Ingår i: Molecular Cancer Therapeutics. - 1535-7163 .- 1538-8514. ; 6:10, s. 2634-2641
  • Tidskriftsartikel (refereegranskat)abstract
    • The MYCN protooncogene is involved in the control of cell proliferation, differentiation, and survival of neuroblasts. Deregulation of MYCN by gene amplification contributes to neuroblastoma development and is strongly correlated to advanced disease and poor outcome, emphasizing the urge for new therapeutic strategies targeting MYCN function. The transcription factor N-Myc, encoded by MYCN, regulates numerous genes together with its partner Max, which also functions as a cofactor for the Mad/Mnt family of Myc antagonists/transcriptional repressors. We and others have previously reported that IFN-gamma synergistically potentiates retinoic acid (RA)induced sympathetic differentiation and growth inhibition in neuroblastoma cells. This study shows that combined treatment of MYCN-amplified neuroblastorna cells with RA+IFN-gamma down-regulates N-Myc protein expression through increased protein turnover, up-regulates Mad1 mRNA and protein, and reduces N-Myc/Max heteroclimerization. This results in a shift of occupancy at the ornithine decarboxylase N-Myc/Mad1 target promoter in vivo from N-Myc/Max to Madl/Max predominance, correlating with histone H4 deacetylation, indicative of a chromatin structure typical of a transcriptionally repressed state. This is further supported by data showing that RA + IFN-gamma treatment strongly represses expression of N-Myc/Mad1 target genes ornithine decarboxylase and hTERT. Our results suggest that combined IFN-gamma and RA signaling can form a basis for new therapeutic strategies targeting N-Myc function for patients with high-risk, MYCN-amplified neuroblastoma.
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4.
  • Guzhova, Irina, et al. (författare)
  • Interferon-gamma cooperates with retinoic acid and phorbol ester to induce differentiation and growth inhibition of human neuroblastoma cells
  • 2001
  • Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 94:1, s. 97-108
  • Tidskriftsartikel (refereegranskat)abstract
    • The prognosis of patients with advanced stages of neuroblastoma with N-myc amplification remains poor despite escalated therapy, a situation that has called for alternative therapeutic approaches. Neuroblastoma cells, which represent immature peripheral neuronal cells, treated with certain physiologic and nonphysiologic agents such as retinoic acid (RA), phorbol esters and interferons (IFN) in vitro undergo cellular differentiation and stop to divide, a process that mimics normal neuronal development. Such "differentiation therapy" using RA after autologous bone marrow transplantation has recently given encouraging results in neuroblastoma patients with advanced disease. Considering approaches for improved differentiation therapy, we investigated possible synergistic effects of combining agents known to influence neuroblastoma growth and differentiation in vitro. Our results show that combined treatment with IFN-gamma and RA or the phorbol ester 12-O-tetradecanoyl-phorbol acetate (TPA) had synergistic or enhancing effects on morphologic differentiation and neurite outgrowth in 5 of 5 neuroblastoma cell lines, 3 of which expressed very high levels of N-myc mRNA due to N-myc amplification. The combinations RA+IFN-gamma or TPA+IFN-gamma also enhanced induced growth inhibition in all 5 cell lines, in several cases resulting in complete growth arrest under conditions where cells stimulated with either agent alone continued to grow. The phenotypic effects of the combined RA+IFN-gamma or TPA+IFN-gamma treatments were in most, but not all, investigated cases accompanied by moderate reductions in N-myc expression, suggesting that the cooperative signals may counteract N-Myc activity at several levels. The cooperativity between IFN-gamma and other differentiation signals may be relevant for approaches to improve the therapy for high-risk neuroblastoma with N-myc-amplification.
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5.
  • Kazi, Julhash U., et al. (författare)
  • The tyrosine kinase CSK associates with FLT3 and c-Kit receptors and regulates downstream signaling.
  • 2013
  • Ingår i: Cellular Signalling. - : Elsevier BV. - 1873-3913 .- 0898-6568. ; 25:9, s. 1852-1860
  • Tidskriftsartikel (refereegranskat)abstract
    • Type III receptor tyrosine kinases (RTKs), FLT3 and c-Kit play important roles in a variety of cellular processes. A number of SH2-domain containing proteins interact with FLT3 and c-Kit and regulate downstream signaling. The SH2-domain containing non-receptor protein tyrosine kinase CSK is mainly studied in context of regulating Src family kinases. Here we present an addition role of this kinase in RTK signaling. We show that CSK interacts with FLT3 and c-Kit in a phosphorylation dependent manner. This interaction is facilitated through the SH2-domain of CSK. Under basal conditions CSK is mainly localized throughout the cytosolic compartment but upon ligand stimulation it is recruited to the inner side of cell membrane. CSK association did not alter receptor ubiquitination or phosphorylation but disrupted downstream signaling. Selective depletion of CSK using siRNA, or inhibition with CSK inhibitor, led to increased phosphorylation of Akt and Erk, but not p38, upon FLT3 ligand (FL) stimulation. Stem cell factor (SCF)-mediated Akt and Erk activation was also elevated by CSK inhibition. However, siRNA mediated CSK knockdown increased SCF stimulated Akt phosphorylation but decreased Erk phosphorylation. CSK depletion also significantly increased both FL- and SCF-induced SHC, Gab2 and SHP2 phosphorylation. Furthermore, CSK depletion contributed to oncogenic FLT3- and c-Kit-mediated cell proliferation, but not to cell survival. Thus, the results indicate that CSK association with type III RTKs, FLT3 and c-Kit can have differential impact on receptor downstream signaling.
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6.
  • Munksgaard Persson, Matilda, et al. (författare)
  • HIF-2 alpha Expression Is Suppressed in SCLC Cells, Which Survive in Moderate and Severe Hypoxia When HIF-1 alpha Is Repressed
  • 2012
  • Ingår i: American Journal of Pathology. - : Elsevier. - 0002-9440 .- 1525-2191. ; 180:2, s. 494-504
  • Tidskriftsartikel (refereegranskat)abstract
    • Small cell lung carcinoma (SCLC) is extremely aggressive and frequently metastasizes widely in its early stage. Because tumor hypoxia is related to aggressive tumor behavior and the hypoxic adaptation of SCLC is poorly documented, we stained SCLC tumors arranged in a tissue microarray for hypoxia-inducible factor (HIF)-1 alpha and HIF-2 alpha proteins. We found an overall lack of HIF-2 alpha protein expression, which was confirmed in large tumor sections. HIF-1 alpha protein was strongly expressed in most tumors, frequently adjacent to necrotic regions. In concordance, cultured SCLC but not non-small cell lung carcinoma cells showed no or extremely low levels of HIF-2 alpha mRNA and no HIF-2 alpha protein at hypoxia. HIF-1 alpha was stabilized after 4 hours at hypoxia, and its accumulation increased up to 96 hours. SCLC cells survived well and showed net proliferation and low cell death in modest (1% oxygen) and severe (0.1% oxygen) hypoxia. HIF-1 alpha repression virtually did not influence cell death or viability despite reduced levels of hypoxia-inducible genes, such as BNIP3 and BNIP3L. At 1% oxygen no increased autophagy (LC3B-II activation) or NF-kappa B signaling were detected, whereas the unfolded protein response was activated at severe hypoxia. Our data indicate that HIFs are not exclusively required for SCLC cell survival at modest or severe hypoxia and that additional, yet uncharacterized, hypoxia-driven adaptation pathways may become activated.
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7.
  • Pedersen, Malin, et al. (författare)
  • 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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8.
  • 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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9.
  • 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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  • Resultat 1-9 av 9

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