Evidence for a p27 tumor suppressive function independent of its role regulating cell proliferation in the prostate Journal Article
| Authors: | Shaffer, D. R.; Viale, A.; Ishiwata, R.; Leversha, M.; Olgac, S.; Manova, K.; Satagopan, J.; Scher, H.; Koff, A. |
| Article Title: | Evidence for a p27 tumor suppressive function independent of its role regulating cell proliferation in the prostate |
| Abstract: | Reduced p27 levels correlate with poor prognosis in a wide spectrum of human tumors and can accelerate tumorigenesis in mouse tissues. To determine whether p27 deficiency can accelerate tumorigenesis in tissues with inactive Rb and p53 pathways, we examined the effect of p27 status on prostate tumorigenesis in mice expressing simian virus 40 large T antigen (LT). In p27-deficient mice expressing LT, tumors progressed from high-grade prostatic intraepithelial neoplasia to poorly differentiated carcinoma at a greatly accelerated rate. p27 deficiency could not collaborate with a mutant of LT that fails to inactivate the Rb pathway alone. Furthermore, p27 deficiency does not increase the proliferation index, reduce the apoptotic index, or affect the expression of E2F-dependent genes in cells expressing LT at any stage of the disease. Expression of LT alone leads to maximal proliferation, but p27 deficiency still increases the amount of cyclin A and cyclin-dependent kinase 2-associated kinase activity in tissues. Interestingly, this model recapitulates an important feature of the human disease, specifically a high frequency of allelic loss of chromosome 16q, which is syntenic to mouse chromosome 8. Loss of heterozygosity may accelerate the inactivation of other tumor suppressors, such as E-cadherin, which are located in this interval. These experiments provide direct physiological and causal evidence that p27 has tumor suppressive functions independent of its role regulating cell proliferation. |
| Keywords: | controlled study; nonhuman; cancer staging; cancer grading; mutant protein; protein function; antigen expression; cell proliferation; mouse; animals; cell cycle proteins; mice; animal tissue; cell division; apoptosis; gene expression; animal experiment; animal model; enzyme activity; carcinogenesis; animalia; prostate cancer; prostatic neoplasms; cancer inhibition; prostate; genomic instability; transcription factor e2f; protein p27; cyclin-dependent kinase inhibitor p27; tumor suppressor proteins; virus large t antigen; simian virus 40; prostatic intraepithelial neoplasia; protein deficiency; chromosome aberrations; tumor growth; mouse models; cyclin a; retinoblastoma protein; disease exacerbation; prostate carcinoma; cyclin dependent kinase 2; cyclin-dependent kinase 2; p27kip1; antigens, viral, tumor; simiae; cdc2-cdc28 kinases; simian virus |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 102 |
| Issue: | 1 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2005-01-04 |
| Start Page: | 210 |
| End Page: | 215 |
| Language: | English |
| DOI: | 10.1073/pnas.0407362102 |
| PUBMED: | 15615849 |
| PROVIDER: | scopus |
| PMCID: | PMC539141 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 30" - "Export Date: 24 October 2012" - "CODEN: PNASA" - "Source: Scopus" |
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