MUC1-C oncoprotein induces TCF7L2 transcription factor activation and promotes cyclin D1 expression in human breast cancer cells.
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ABSTRACT:
SUBMITTER: Rajabi H
PROVIDER: S-EPMC3322974 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Blasts from approximately one-third of patients with acute myeloid leukemia (AML) harbor activating mutations in the FMS-like tyrosine kinase 3 (FLT3) receptor tyrosine kinase that confer a poor prognosis. The Mucin 1-C-terminal subunit (MUC1-C) oncoprotein is aberrantly expressed in AML blasts and stem cells; however, there is no known interaction between MUC1-C and FLT3. The present studies demonstrate that MUC1-C associates with wild-type and mutant FLT3 in AML cells. Targeting MUC1-C with the cell-penetrating peptide inhibitor GO-203 disrupts MUC1-C/FLT3 complexes and downregulates FLT3 activation. GO-203 treatment of AML cells was also associated with inhibition of the FLT3 downstream effectors AKT, extracellular signal-regulated kinase, and STAT5. The results further show that AML cells with FLT3-activating mutations and resistant to the FLT3 inhibitor midostaurin/PKC412 are sensitive to GO-203-induced growth arrest and death. Moreover, GO-203 increases sensitivity of mutant FLT3 AML cells to FLT3 inhibitor treatment. These results indicate that MUC1-C contributes to FLT3 activation in AML cells and that targeting MUC1-C inhibits the FLT3 signaling pathway. Our findings support the development of MUC1-C inhibitors alone and in combination with agents that target FLT3 for the treatment of wild-type and mutant FLT3 AML.
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Project description:Proteomic analysis of castration-resistant prostate cancer demonstrated the enrichment of Src tyrosine kinase activity in approximately 90% of patients. Src is known to induce cyclin D1, and a cyclin D1-regulated gene expression module predicts poor outcome in human prostate cancer. The tumor-associated calcium signal transducer 2 (TACSTD2/Trop2/M1S1) is enriched in the prostate, promoting prostate stem cell self-renewal upon proteolytic activation via a γ-secretase cleavage complex (PS1, PS2) and TACE (ADAM17), which releases the Trop2 intracellular domain (Trop2 ICD). Herein, v-Src transformation of primary murine prostate epithelial cells increased the proportion of prostate cancer stem cells as characterized by gene expression, epitope characteristics, and prostatosphere formation. Cyclin D1 was induced by v-Src, and Src kinase induction of Trop2 ICD nuclear accumulation required cyclin D1. Cyclin D1 induced abundance of the Trop2 proteolytic cleavage activation components (PS2, TACE) and restrained expression of the inhibitory component of the Trop2 proteolytic complex (Numb). Patients with prostate cancer with increased nuclear Trop2 ICD and cyclin D1, and reduced Numb, had reduced recurrence-free survival probability (HR = 4.35). Cyclin D1, therefore, serves as a transducer of v-Src-mediated induction of Trop2 ICD by enhancing abundance of the Trop2 proteolytic activation complex. Cancer Res; 76(22); 6723-34. ©2016 AACR.
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Project description:Nuclear factor-kappaB (NF-kappaB) is constitutively activated in diverse human malignancies. The mucin 1 (MUC1) oncoprotein is overexpressed in human carcinomas and, like NF-kappaB, blocks cell death and induces transformation. The present studies show that MUC1 constitutively associates with NF-kappaB p65 in carcinoma cells. The MUC1 COOH-terminal subunit (MUC1-C) cytoplasmic domain binds directly to NF-kappaB p65 and, importantly, blocks the interaction between NF-kappaB p65 and its inhibitor IkappaBalpha. We show that NF-kappaB p65 and MUC1-C constitutively occupy the promoter of the Bcl-xL gene in carcinoma cells and that MUC1-C contributes to NF-kappaB-mediated transcriptional activation. Studies in nonmalignant epithelial cells show that MUC1-C interacts with NF-kappaB in the response to tumor necrosis factor-alpha stimulation. Moreover, tumor necrosis factor-alpha induces the recruitment of NF-kappaB p65-MUC1-C complexes to NF-kappaB target genes, including the promoter of the MUC1 gene itself. We also show that an inhibitor of MUC1-C oligomerization blocks the interaction with NF-kappaB p65 in vitro and in cells. The MUC1-C inhibitor decreases MUC1-C and NF-kappaB p65 promoter occupancy and expression of NF-kappaB target genes. These findings indicate that MUC1-C is a direct activator of NF-kappaB p65 and that an inhibitor of MUC1 function is effective in blocking activation of the NF-kappaB pathway.
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Project description:OBJECTIVES:Control of cell proliferation is critical for accurate cell differentiation and tissue formation, during development and regeneration. Here, we have analysed the role of microphthalmia-associated transcription factor MITF and its direct target, T-box factor TBX2, in regulating proliferation of mammalian neural crest-derived melanocytes. MATERIALS AND METHODS:Immunohistochemistry was used to examine spatial and temporal expression of TBX2 in melanocytes in vivo. RNAi and cell proliferation analysis were used to investigate functional roles of TBX2. Furthermore, quantitative RT-PCR, western blot analysis and flow cytometry were used to further scrutinize molecular mechanisms underlying TBX2-dependent cell proliferation. RESULTS:TBX2 was found to be co-expressed with MITF in melanocytes of mouse hair follicles. Specific Tbx2 knockdown in primary neural crest cells led to inhibition MITF-positive melanoblast proliferation. Tbx2 knockdown in melan-a cells led to reduction in Cyclin D1 expression and G1-phase cell cycle arrest. TBX2 directly activated Ccnd1 transcription by binding to a specific sequence in the Ccnd1 promoter, and the defect in cell proliferation could be rescued partially by overexpression of Cyclin D1 in Tbx2 knockdown melanocytes. CONCLUSIONS:Results suggest that the Mitf-Tbx2-Cyclin D1 pathway played an important role in regulation of melanocyte proliferation, and provided novel insights into the complex physiology of melanocytes.
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