| 1. |
- Bahram, Fuad, et al.
(author)
-
Interferon-γ-induced p27KIP1 binds to and targets MYC for proteasome-mediated degradation.
- 2016
-
In: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 7:3, s. 2837-2854
-
Journal article (peer-reviewed)abstract
- The Myc oncoprotein is tightly regulated at multiple levels including ubiquitin-mediated protein turnover. We recently demonstrated that inhibition of Cdk2-mediated phosphorylation of Myc at Ser-62 pharmacologically or through interferon (IFN)-γ-induced expression of p27Kip1 (p27) repressed Myc's activity to suppress cellular senescence and differentiation. In this study we identified an additional activity of p27 to interfere with Myc independent of Ser-62 phosphorylation. p27 is required and sufficient for IFN-γ-induced turnover of Myc. p27 interacted with Myc in the nucleus involving the C-termini of the two proteins, including Myc box 4 of Myc. The C-terminus but not the Cdk2 binding fragment of p27 was sufficient for inducing Myc degradation. Protein expression data of The Cancer Genome Atlas breast invasive carcinoma set revealed significantly lower Myc protein levels in tumors with highly expressed p27 lacking phosphorylation at Thr-157 - a marker for active p27 localized in the nucleus. Further, these conditions correlated with favorable tumor stage and patient outcome. This novel regulation of Myc by IFN-γ/p27KIP1 potentially offers new possibilities for therapeutic intervention in tumors with deregulated Myc.
|
|
| 2. |
|
|
| 3. |
- Castell, Alina, et al.
(author)
-
MYCMI-7 : A Small MYC-Binding Compound that Inhibits MYC: MAX Interaction and Tumor Growth in a MYC-Dependent Manner
- 2022
-
In: Cancer Research Communications. - : American Association For Cancer Research (AACR). - 2767-9764. ; 2:3, s. 182-201
-
Journal article (peer-reviewed)abstract
- Deregulated expression of MYC family oncogenes occurs frequently in human cancer and is often associated with aggressive disease and poor prognosis. While MYC is a highly warranted target, it has been considered "undruggable," and no specific anti-MYC drugs are available in the clinic. We recently identified molecules named MYCMIs that inhibit the interaction between MYC and its essential partner MAX. Here we show that one of these molecules, MYCMI-7, efficiently and selectively inhibits MYC:MAX and MYCN:MAX interactions in cells, binds directly to recombinant MYC, and reduces MYC-driven transcription. In addition, MYCMI-7 induces degradation of MYC and MYCN proteins. MYCMI-7 potently induces growth arrest/apoptosis in tumor cells in a MYC/MYCN-dependent manner and downregulates the MYC pathway on a global level as determined by RNA sequencing. Sensitivity to MYCMI-7 correlates with MYC expression in a panel of 60 tumor cell lines and MYCMI-7 shows high efficacy toward a collection of patient-derived primary glioblastoma and acute myeloid leukemia (AML) ex vivo cultures. Importantly, a variety of normal cells be- come G1 arrested without signs of apoptosis upon MYCMI-7 treatment. Finally, in mouse tumor models of MYC-driven AML, breast cancer, and MYCN-amplified neuroblastoma, treatment with MYCMI-7 downregu- lates MYC/MYCN, inhibits tumor growth, and prolongs survival through apoptosis with few side effects. In conclusion, MYCMI-7 is a potent and selective MYC inhibitor that is highly relevant for the development into clinically useful drugs for the treatment of MYC-driven cancer.Significance: Our findings demonstrate that the small-molecule MYCMI-7 binds MYC and inhibits interaction between MYC and MAX, thereby ham- pering MYC-driven tumor cell growth in culture and in vivo while sparing normal cells.
|
|
| 4. |
- Cheng, Liqin, et al.
(author)
-
A MicroRNA Gene Panel Predicts the Vaginal Microbiota Composition
- 2021
-
In: mSystems. - : American Society for Microbiology. - 2379-5077. ; 6:3
-
Journal article (peer-reviewed)abstract
- The vaginal microbiota plays an essential role in vaginal health. The vaginas of many reproductive-age women are dominated by one of the Lactobacillus species. However, the vaginas of a large number of women are characterized by the colonization of several other anaerobes. Notably, some women with the non-Lactobacillus-dominated vaginal microbiota develop bacterial vaginosis, which has been correlated with sexually transmitted infections and other adverse outcomes. However, interactions and mechanisms linking the vaginal microbiota to host response are still under investigation. There are studies suggesting a link between human microRNAs and gut microbiota, but limited analysis has been carried out on the interplay of microRNAs and vaginal microbiota. In this study, we performed a microRNA expression array profiling on 67 vaginal samples from young Swedish women. MicroRNAs were clustered into distinct groups according to vaginal microbiota composition. Interestingly, 182 microRNAs were significantly elevated in their expression in the non-Lactobacillus-dominated community, suggesting an antagonistic relationship between Lactobacillus and microRNAs. Of the elevated microRNAs, 10 microRNAs displayed excellent diagnostic potential, visualized by receiver operating characteristics analysis. We further validated our findings in 34 independent samples where expression of top microRNA candidates strongly separated the Lactobacillus-dominated community from the non-Lactobacillus-dominated community in the vaginal microbiota. Notably, the Lactobacillus crispatus-dominated community showed the most profound differential microRNA expression compared with the non-Lactobacillus-dominated community. In conclusion, we demonstrate a strong relationship between the vaginal microbiota and numerous genital microRNAs, which may facilitate a deeper mechanistic interplay in this biological niche. IMPORTANCE Vaginal microbiota is correlated with women's health, where a non-Lactobacillus-dominated community predisposes women to a higher risk of disease, including human papillomavirus (HPV). However, the molecular relationship between the vaginal microbiota and host is largely unexplored. In this study, we investigated a link between the vaginal microbiota and host microRNAs in a group of young women. We uncovered an inverse correlation of the expression of microRNAs with the abundance of Lactobacillus species in the vaginal microbiota. Particularly, the expression of microRNA miR-23a-3p and miR-130a-3p, displaying significantly elevated levels in non-Lactobacillus-dominated communities, predicted the bacterial composition of the vaginal microbiota in an independent validation group. Since targeting of microRNAs is explored in the clinical setting, our results warrant investigation of whether microRNA modulation could be used for treating vaginosis recurrence and vaginosis-related diseases. Conversely, commensal bacteria could be used for treating diseases with microRNA aberrations.
|
|
| 5. |
- Hydbring, Per
(author)
-
Modulating the activity of the c-Myc oncoprotein : implications for therapeutic treatment
- 2009
-
Doctoral thesis (other academic/artistic)abstract
- The Myc oncoprotein regulates numerous cellular processes and is frequently deregulated in cancer due to genetic lesions. However, in addition to its tumor promoting activity, Myc and other oncoproteins induce intrinsic safe-guard mechanisms against tumorigenesis like apoptosis and cellular senescence, which have to be overcome by additional genetic lesions for cellular transformation. In this work, we identify ways of reactivating these anti-tumorigenic pathways in cells with deregulated Myc. First, we uncover an unexpected capacity of transforming growth factor-β (TGF-β) to force hematopoietic cells with deregulated Myc into cellular senescence despite continuous Myc expression. This involved upregulation of the Myc antagonist Mad1, leading to repressed transcription of Myc target genes. We further reveal a novel role of Myc in Myc/Ras dependent transformation. While Ras induced cellular senescence and suppressed Myc-activated apoptosis, we found that Myc repressed Ras-induced senescence. This required phosphorylation of Myc at Ser-62 by cyclin dependent kinase 2 (Cdk2). Further, pharmacological inhibitors of Cdk2 forced Myc+Ras expressing cells into senescence. In addition, although redundant for cell cycle progression, Cdk2 was shown to have a unique role in suppressing Myc-induced senescence, and depletion of Cdk2 in a mouse Eµ-myc lymphoma model led to regression of tumor development. Taken together, this highlights Cdk2-targeting in Myc and Ras-driven tumors. Finally, we uncover a novel interplay between Myc and the protein deacetylase SIRT1. While Myc induced SIRT1 expression and activity, SIRT1 fed back to Myc by stabilizing the Myc protein. Further, SIRT1 repressed Myc-induced apoptosis and senescence, pointing out SIRT1 as a promising target in neoplasia driven by Myc. In summary, this thesis demonstrates potential new strategies for therapeutic intervention of tumors with deregulated Myc by targeting its essential cofactors and collaboration partners.
|
|
| 6. |
- Söderberg, Ola, et al.
(author)
-
Direct observation of individual endogenous protein complexes in situ by proximity ligation
- 2006
-
In: Nature Methods. - : Springer Science and Business Media LLC. - 1548-7091 .- 1548-7105. ; 3:12, s. 995-1000
-
Journal article (peer-reviewed)abstract
- Cellular processes can only be understood as the dynamic interplay of molecules. There is a need for techniques to monitor interactions of endogenous proteins directly in individual cells and tissues to reveal the cellular and molecular architecture and its responses to perturbations. Here we report our adaptation of the recently developed proximity ligation method to examine the subcellular localization of protein-protein interactions at single-molecule resolution. Proximity probes-oligonucleotides attached to antibodies against the two target proteins-guided the formation of circular DNA strands when bound in close proximity. The DNA circles in turn served as templates for localized rolling-circle amplification (RCA), allowing individual interacting pairs of protein molecules to be visualized and counted in human cell lines and clinical specimens. We used this method to show specific regulation of protein-protein interactions between endogenous Myc and Max oncogenic transcription factors in response to interferon-gamma (IFN-gamma) signaling and low-molecular-weight inhibitors.
|
|
| 7. |
- Tsakonas, Georgios, et al.
(author)
-
An immune gene expression signature distinguishes central nervous system metastases from primary tumours in non-small-cell lung cancer
- 2020
-
In: European Journal of Cancer. - : ELSEVIER SCI LTD. - 0959-8049 .- 1879-0852. ; 132, s. 24-34
-
Journal article (peer-reviewed)abstract
- Background: Dissemination of non-small-cell lung cancer (NSCLC) in the central nervous system is a frequent and challenging clinical problem. Systemic or local therapies rarely prolong survival and have modest activity regarding local control. Alterations in gene expression in brain metastasis versus primary tumour may increase aggressiveness and impair therapeutic efforts.Methods: We identified 25 patients with surgically removed NSCLC brain metastases in two different patient cohorts. For 13 of these patients, primary tumour samples were available. Gene expression analysis using the nCounter (R) PanCancer Immune Profiling gene expression panel (nanoString technologies Inc.) was performed in brain metastases and primary tumour samples. Identification of differentially expressed genes was conducted on normalized data using the nSolver analysis software.Results: We compared gene expression patterns in brain metastases with primary tumours. Brain metastasis samples displayed a distinct clustering pattern compared to primary tumour samples with a statistically significant downregulation of genes related to immune response and immune cell activation. Results from KEGG term analysis on differentially expressed genes revealed a concomitant enrichment of multiple KEGG terms associated with the immune system. We identified a 12-gene immune signature that clearly separated brain metastases from primary tumours.Conclusions: We identified a unique gene downregulation pattern in brain metastases compared with primary tumours. This finding may explain the lower intracranial efficacy of systemic therapy, especially immunotherapy, in brain metastasis of patients with NSCLC.
|
|
| 8. |
- Tsakonas, Georgios, et al.
(author)
-
Matched Analyses of Brain Metastases versus Primary Non-Small Cell Lung Cancer Reveal a Unique microRNA Signature
- 2023
-
In: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 24:1
-
Journal article (peer-reviewed)abstract
- Distant spreading of tumor cells to the central nervous system in non-small cell lung cancer (NSCLC) occurs frequently and poses major clinical issues due to limited treatment options. RNAs displaying differential expression in brain metastasis versus primary NSCLC may explain distant tumor growth and may potentially be used as therapeutic targets. In this study, we conducted systematic microRNA expression profiling from tissue biopsies of primary NSCLC and brain metastases from 25 patients. RNA analysis was performed using the nCounter Human v3 miRNA Expression Assay, NanoString technologies, followed by differential expression analysis and in silico target gene pathway analysis. We uncovered a panel of 11 microRNAs with differential expression and excellent diagnostic performance in brain metastasis versus primary NSCLC. Five microRNAs were upregulated in brain metastasis (miR-129-2-3p, miR-124-3p, miR-219a-2-3p, miR-219a-5p, and miR-9-5p) and six microRNAs were downregulated in brain metastasis (miR-142-3p, miR-150-5p, miR-199b-5p, miR-199a-3p, miR-199b-5p, and miR-199a-5p). The differentially expressed microRNAs were predicted to converge on distinct target gene networks originating from five to twelve core target genes. In conclusion, we uncovered a unique microRNA profile linked to two target gene networks. Our results highlight the potential of specific microRNAs as biomarkers for brain metastasis in NSCLC and indicate plausible mechanistic connections.
|
|
| 9. |
|
|
| 10. |
- Wu, Siqin, et al.
(author)
-
TGF-beta enforces senescence in Myc-transformed hematopoietic tumor cells through induction of Mad1 and repression of Myc activity
- 2009
-
In: Experimental Cell Research. - : Elsevier BV. - 0014-4827 .- 1090-2422. ; 315:18, s. 3099-3111
-
Journal article (peer-reviewed)abstract
- Inhibition of tumor growth factor (TGF)-beta-mediated cell cycle exit is considered an important tumorigenic function of Myc oncoproteins. Here we found that TGF-beta1 enforced G(1) cell cycle arrest and cellular senescence in human U-937 myeloid tumor cells ectopically expressing v-Myc, which contains a stabilizing mutation frequently found in lymphomas. This correlated with induced expression of the Myc antagonist Mad1, resulting in replacement of Myc for Mad1 at target promoters, reduced histone acetylation and strong repression of Myc-driven transcription. The latter was partially reversed by histone deacetylase (HDAC) inhibitors, consistent with involvement of Mad1. Importantly, knockdown of MAD1 expression prevented TGF-beta1-induced senescence, underscoring that Mad1 is a crucial component of this process. Enforced Mad1 expression sensitized U-937-myc cells to TGF-beta and restored phorbol ester-induced cell cycle exit, but could not alone induce G(1) arrest, suggesting that Mad1 is required but not sufficient for cellular senescence. Our results thus demonstrate that TGF-beta can override Myc activity despite a stabilizing cancer mutation and induce senescence in myeloid tumor cells, at least in part by induction of Mad1. TGF-beta-induced senescence, or signals mimicking this pathway, could therefore potentially be explored as a therapeutic principle for treating hematopoietic and other tumors with deregulated MYC expression.
|
|
