Skp2 is required for survival of aberrantly proliferating Rb1-deficient cells and for tumorigenesis in Rb1+/ mice

Department of Developmental and Molecular Biology and Medicine, The Albert Einstein Comprehensive Cancer Center and Liver Research Center, Albert Einstein College of Medicine, Bronx, New York, USA.
Nature Genetics (Impact Factor: 29.35). 12/2009; 42(1):83-8. DOI: 10.1038/ng.498
Source: PubMed


Heterozygosity of the retinoblastoma gene Rb1 elicits tumorigenesis in susceptible tissues following spontaneous loss of the remaining functional allele. Inactivation of previously studied retinoblastoma protein (pRb) targets partially inhibited tumorigenesis in Rb1(+/-) mice. Here we report that inactivation of pRb target Skp2 (refs. 7,8) completely prevents spontaneous tumorigenesis in Rb1(+/-) mice. Targeted Rb1 deletion in melanotrophs ablates the entire pituitary intermediate lobe when Skp2 is inactivated. Skp2 inactivation does not inhibit aberrant proliferation of Rb1-deleted melanotrophs but induces their apoptotic death. Eliminating p27 phosphorylation on T187 in p27T187A knock-in mice reproduces the effects of Skp2 knockout, identifying p27 ubiquitination by SCF(Skp2) ubiquitin ligase as the underlying mechanism for Skp2's essential tumorigenic role in this setting. RB1-deficient human retinoblastoma cells also undergo apoptosis after Skp2 knockdown; and ectopic expression of p27, especially the p27T187A mutant, induces apoptosis. These results reveal that Skp2 becomes an essential survival gene when susceptible cells incur Rb1 deficiency.

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    • "In particular, pRb-deficient cancer cells are sensitized to apoptosis induced by Skp2 silencing with no effect on proliferation. These results suggest that Skp2 has a role in cell survival, which is independent from its role in cell proliferation (Wang et al., 2010a). Interestingly, high Skp2 expression was implicated in T cell lymphoma in mice and in high-grade lymphomas in human (Latres et al., 2001). "
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    • "Module 143 is composed of cyclins regulating the cell cycle and a link to telomere formation (E2F5). SKP2 is a known oncogene and interacts with cyclins to promote cell proliferation and evade apoptosis [51]. SKP2 and cyclin CCNA2 show significantly altered activity and interact with G2-phase cell cycle checkpoint genes BRCA2 via CDK2. "
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    • "Moreover, Skp2 overexpression was found to promote cancer invasion and metastasis, whereas its deficiency inhibits these processes (Chan et al., 2010a). Using transgenic mouse models, we and others have illustrated that Skp2 is required for cancer development in multiple tumorpromoting conditions and that Skp2 deficiency triggers p53- independent, p27-dependent cellular senescence/apoptosis but inhibits Akt-mediated glycolysis (Chan et al., 2012; Lin et al., 2010; Wang et al., 2010). Collectively, these studies suggest that targeting Skp2 is a promising strategy for cancer treatment, thereby calling for an urgent need to develop specific Skp2 inhibitors. "
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