Myc-enhanced expression of Cul1 promotes ubiquitin-dependent proteolysis and cell cycle progression

RC O'Hagan, M Ohh, G David… - Genes & …, 2000 - genesdev.cshlp.org
RC O'Hagan, M Ohh, G David, IM De Alboran, FW Alt, WG Kaelin, RA DePinho
Genes & development, 2000genesdev.cshlp.org
The c-Myc oncoprotein plays an important role in the growth and proliferation of normal and
neoplastic cells. To execute these actions, c-Myc is thought to regulate functionally diverse
sets of genes that directly govern cellular mass and progression through critical cell cycle
transitions. Here, we provide several lines of evidence that c-Myc promotes ubiquitin-
dependent proteolysis by directly activating expression of the Cul1 gene, encoding a critical
component of the ubiquitin ligase SCFSKP2. The cell cycle inhibitor p27kip1 is a known …
The c-Myc oncoprotein plays an important role in the growth and proliferation of normal and neoplastic cells. To execute these actions, c-Myc is thought to regulate functionally diverse sets of genes that directly govern cellular mass and progression through critical cell cycle transitions. Here, we provide several lines of evidence that c-Myc promotes ubiquitin-dependent proteolysis by directly activating expression of the Cul1 gene, encoding a critical component of the ubiquitin ligase SCFSKP2. The cell cycle inhibitor p27kip1 is a known target of the SCFSKP2 complex, and Myc-induced Cul1 expression matched well with the kinetics of declining p27kip1 protein. Enforced Cul1 expression or antisense neutralization of p27kip1 was capable of overcoming the slow-growth phenotype of c-Myc null primary mouse embryonic fibroblasts (MEFs). In reconstitution assays, the addition of in vitro translated Cul1 protein alone was able to restore p27kip1ubiquitination and degradation in lysates derived fromc-myc −/− MEFs or density-arrested human fibroblasts. These functional and biochemical data provide a direct link between c-Myc transcriptional regulation and ubiquitin-mediated proteolysis and together support the view that c-Myc promotes G1 exit in part via Cul1-dependent ubiquitination and degradation of the CDK inhibitor, p27kip1.
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