| Title | A prostatic intraepithelial neoplasia-dependent p27 Kip1 checkpoint induces senescence and inhibits cell proliferation and cancer progression. |
| Publication Type | Journal Article |
| Year of Publication | 2008 |
| Authors | Majumder PK, Grisanzio C, O'Connell F, Barry M, Brito JM, Xu Q, Guney I, Berger R, Herman P, Bikoff R, Fedele G, Baek W-K, Wang S, Ellwood-Yen K, Wu H, Sawyers CL, Signoretti S, Hahn WC, Loda M, Sellers WR |
| Journal | Cancer Cell |
| Volume | 14 |
| Issue | 2 |
| Pagination | 146-55 |
| Date Published | 2008 Aug 12 |
| ISSN | 1878-3686 |
| Keywords | Alleles, Animals, Animals, Genetically Modified, Biomarkers, Cell Adhesion, Cell Communication, Cell Line, Cell Polarity, Cell Proliferation, Cellular Senescence, Cyclin-Dependent Kinase Inhibitor p27, Disease Progression, Epithelial Cells, Humans, Male, Mice, Mutation, Phenotype, Prostatic Intraepithelial Neoplasia, Prostatic Neoplasms, Protein Kinases, Proto-Oncogene Proteins c-akt, Rats, TOR Serine-Threonine Kinases |
| 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 p27(Kip1) and senescence. Genetic ablation of p27(Kip1) led to downregulation of senescence markers and progression to cancer. In humans, p27(Kip1) 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, p27(Kip1) 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 p27(Kip1)-driven checkpoint limits progression of PIN to CaP. |
| DOI | 10.1016/j.ccr.2008.06.002 |
| Alternate Journal | Cancer Cell |
| PubMed ID | 18691549 |
| PubMed Central ID | PMC2583442 |
| Grant List | P01 CA89021 / CA / NCI NIH HHS / United States K01 CA94223 / CA / NCI NIH HHS / United States |
Related Lab:
Related Faculty:
Massimo Loda, M.D.