Skp2 is required for survival of aberrantly proliferating Rb1-deficient cells and for tumorigenesis in Rb1+/ mice Journal Article
| Authors: | Wang, H.; Bauzon, F.; Ji, P.; Xu, X.; Sun, D.; Locker, J.; Sellers, R. S.; Nakayama, K.; Nakayama, K. I.; Cobrinik, D.; Zhu, L. |
| Article Title: | Skp2 is required for survival of aberrantly proliferating Rb1-deficient cells and for tumorigenesis in Rb1+/ mice |
| Abstract: | 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. © 2010 Nature America, Inc. All rights reserved. |
| Keywords: | controlled study; survival analysis; unclassified drug; gene deletion; mutation; nonhuman; cell proliferation; mouse; animals; mice; mice, knockout; animal tissue; cell death; cell survival; mus; apoptosis; animal experiment; rna interference; retinoblastoma; cell line, tumor; mice, inbred c57bl; time factors; carcinogenesis; mice, inbred strains; chromosome aberration; blotting, western; ubiquitination; reverse transcriptase polymerase chain reaction; protein p27; cyclin-dependent kinase inhibitor p27; neoplasms, experimental; gene inactivation; retinoblastoma protein; mutant; s phase kinase associated protein 2; s-phase kinase-associated proteins; melanotroph; retinoblastoma protein 1; hypophysis; pituitary gland |
| Journal Title: | Nature Genetics |
| Volume: | 42 |
| Issue: | 1 |
| ISSN: | 1061-4036 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2010-01-01 |
| Start Page: | 83 |
| End Page: | 88 |
| Language: | English |
| DOI: | 10.1038/ng.498 |
| PUBMED: | 19966802 |
| PROVIDER: | scopus |
| PMCID: | PMC2990528 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 9" - "Export Date: 20 April 2011" - "CODEN: NGENE" - "Source: Scopus" |
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