A prostatic intraepithelial neoplasia-dependent p27Kip1 checkpoint induces senescence and inhibits cell proliferation and cancer progression Journal Article
| Authors: | Majumder, P. K.; Grisanzio, C.; O'Connell, F.; Barry, M.; Brito, J. M.; Xu, Q.; Guney, I.; Berger, R.; Herman, P.; Bikoff, R.; Fedele, G.; Baek, W. K.; Wang, S.; Ellwood-Yen, K.; Wu, H.; Sawyers, C. L.; Signoretti, S.; Hahn, W. C.; Loda, M.; Sellers, W. R. |
| Article Title: | A prostatic intraepithelial neoplasia-dependent p27Kip1 checkpoint induces senescence and inhibits cell proliferation and cancer progression |
| Abstract: | Transgenic expression of activated AKT1 in the murine prostate induces prostatic intraepithelial neoplasia (PIN) that does not progress to invasive prostate cancer (CaP). In luminal epithelial cells of Akt-driven PIN, we show the concomitant induction of p27Kip1 and senescence. Genetic ablation of p27Kip1 led to downregulation of senescence markers and progression to cancer. In humans, p27Kip1 and senescence markers were elevated in PIN not associated with CaP but were decreased or absent, respectively, in cancer-associated PIN and in CaP. Importantly, p27Kip1 upregulation in mouse and human in situ lesions did not depend upon mTOR or Akt activation but was instead specifically associated with alterations in cell polarity, architecture, and adhesion molecules. These data suggest that a p27Kip1-driven checkpoint limits progression of PIN to CaP. © 2008 Elsevier Inc. All rights reserved. |
| Keywords: | protein kinase b; controlled study; human tissue; protein expression; human cell; mutation; cancer growth; nonhuman; cell proliferation; biological markers; animal cell; mouse; phenotype; animals; mice; animal tissue; cell structure; protein kinases; embryo; cell line; animal experiment; animal model; alleles; enzyme activation; transgenic mouse; prostate cancer; cancer invasion; prostatic neoplasms; cancer inhibition; disease progression; cyclin dependent kinase inhibitor 1b; mammalian target of rapamycin; cyclin-dependent kinase inhibitor p27; rat; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; proto-oncogene proteins c-akt; murinae; epithelium cell; protein induction; epithelial cells; cell polarity; cellcycle; down regulation; gene inactivation; rats; prostatic intraepithelial neoplasia; upregulation; cell interaction; cell adhesion; cell communication; cell aging; polarization; cell adhesion molecule; animals, genetically modified |
| Journal Title: | Cancer Cell |
| Volume: | 14 |
| Issue: | 2 |
| ISSN: | 1535-6108 |
| Publisher: | Cell Press |
| Date Published: | 2008-08-12 |
| Start Page: | 146 |
| End Page: | 155 |
| Language: | English |
| DOI: | 10.1016/j.ccr.2008.06.002 |
| PUBMED: | 18691549 |
| PROVIDER: | scopus |
| PMCID: | PMC2583442 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 44" - "Export Date: 17 November 2011" - "CODEN: CCAEC" - "Source: Scopus" |
