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A prostatic intraepithelial neoplasia-dependent p27 Kip1 checkpoint induces senescence and inhibits cell proliferation and cancer progression.

Majumder, Pradip K and Grisanzio, Chiara and O'Connell, Fionnuala and Barry, Marc and Brito, Joseph M and Xu, Qing and Guney, Isil and Berger, Raanan and Herman, Paula and Bikoff, Rachel and Fedele, Giuseppe and Baek, Won-Ki and Wang, Shunyou and Ellwood-Yen, Katharine and Wu, Hong and Sawyers, Charles L and Signoretti, Sabina and Hahn, William C and Loda, Massimo and Sellers, William (2008) A prostatic intraepithelial neoplasia-dependent p27 Kip1 checkpoint induces senescence and inhibits cell proliferation and cancer progression. Cancer Cell, 14 (2). pp. 146-155. ISSN 1878-3686

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.

Item Type: Article
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Additional Information: author can archive post-print (ie final draft post-refereeing); Publisher's version/PDF cannot be used
Keywords: CaP, prostate cancer; senescence; PIN; Prostate intraepithelial neoplasia; Akt and p27Kip1
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Date Deposited: 14 Dec 2009 13:48
Last Modified: 31 Jan 2013 00:55
URI: https://oak.novartis.com/id/eprint/1342

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