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- W2808058571 abstract "3022 The c-Myc proto-oncogene is a central regulator of key cellular processes such as differentiation, regulation of the G1-to-S-phase transition, proliferation, maintenance of cell size, angiogenesis, and apoptosis. c-Myc is deregulated in a variety of types of cancer, including melanomas, myelomas, Burkitt’s lymphoma, and breast, prostate, and colon cancer, and this deregulation often correlates with highly aggressive, poorly differentiated tumors and poor prognosis. Compounds that inhibit c-Myc activity specifically in tumor cells are being actively sought for possible development as anticancer therapy. In one such search, screening a library of small molecular weight compounds for their ability to induce the degradation of critical transcription factors and tyrosine kinases led to the design and synthesis of WP1130, a compound that reduces Jak2, Bcr/Abl, and c-Myc protein stability. The purpose of this study was to identify the mechanisms mediating the WP1130-induced downregulation of c-Myc. Treatment of multiple myeloma (MM-1) cells with WP1130 led to rapid downregulation of the c-Myc protein (tested by Western blotting) but did not inhibit transcription of c-Myc (tested by Northern blotting). Further, WP1130 did not degrade c-Myc mRNA that had been synthesized in an in-vitro transcription and translation assay. Collectively, these observations indicate that WP1130 downregulates c-Myc by activating a proteolytic pathway. Because endogenous c-myc is degraded by the ubiquitin-mediated proteasomal system, we next investigated whether a similar mechanism mediated WP1130-induced degradation of c-Myc. Indeed, proteasome inhibitors blocked the ability of WP1130 to degrade c-Myc, indicating that WP1130-induced c-Myc degradation depends on the proteasome. To identify the region of c-Myc necessary for its WP1130-induced, proteasome-mediated degradation, we treated HeLa cells that ectopically expressed either wild-type c-Myc or a series of scanning deletion mutants with WP1130 and assessed c-Myc expression by Western blot analysis. Expression of wild-type c-Myc protein and that of all the deletion mutants except one was strongly downregulated in the presence of WP1130. The c-Myc mutant that was unaffected by WP1130 had a deletion at the c-terminus_a region distinct from all others known to be involved in the proteasomal-mediated downregulation of c-Myc. Our ongoing work involves identifying the signaling molecules that participate in this novel, proteasome-dependent pathway." @default.
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- W2808058571 date "2006-04-15" @default.
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- W2808058571 title "Degradation of c-Myc by WP1130 Through Activation of a Novel Proteasomal-Dependent Pathway" @default.
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