Myc-enhanced expression of Cul1 promotes ubiquitin-dependent proteolysis and cell cycle progression
- Rónán C. O'Hagan1,2,
- Michael Ohh1,
- Gregory David1,2,
- Ignacio Moreno de Alboran4,5,
- Frederick W. Alt4,5,
- William G. Kaelin, Jr.1,3, and
- Ronald A. DePinho1,2,6
- 1Department of Adult Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02115 USA; 2 Department of Medicine and Genetics, Harvard Medical School, Boston, Massachusetts 02115 USA; 3 Howard Hughes Medical Institute, Dana Farber Cancer Institute, Boston, Massachusetts 02115 USA; 4 Howard Hughes Medical Institute, Children's Hospital, Boston, Massachusetts 02115 USA; 5 Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115 USA
Abstract
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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Footnotes
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↵6 Corresponding author.
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E-MAIL ron_depinho{at}dfci.harvard.edu; FAX (617) 632-6069
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Article and publication are at www.genesdev.org/cgi/doi/10.1101/gad.827200.
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- Received June 14, 2000.
- Accepted July 10, 2000.
- Cold Spring Harbor Laboratory Press