Journal
GENES & DEVELOPMENT
Volume 14, Issue 17, Pages 2185-2191Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.827200
Keywords
Myc; Cul1; ubiquitin-dependent proteolysis; cell cycle; p27(kip1)
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Funding
- EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH &HUMAN DEVELOPMENT [R01HD028317] Funding Source: NIH RePORTER
- NATIONAL CANCER INSTITUTE [R01CA068490] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [P01AI035714] Funding Source: NIH RePORTER
- NCI NIH HHS [R01 CA068490, R01CA68490] Funding Source: Medline
- NIAID NIH HHS [AI35714, P01 AI035714] Funding Source: Medline
- NICHD NIH HHS [R01HD28317] Funding Source: Medline
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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 Cull gene, encoding a critical component of the ubiquitin ligase SCFSKP2. The cell cycle inhibitor p27(kip1) is a known target of the SCFSKP2 complex, and Myc-induced Cull expression matched well with the kinetics of declining p27(kip1) protein. Enforced Cull expression or antisense neutralization of p27(kip1) 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 Cull protein alone was able to restore p27(kip1) ubiquitination and degradation in lysates derived from c-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 G(1) exit in part via Cul1-dependent ubiquitination and degradation of the CDK inhibitor, p27(kip1).
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