A Prostatic Intraepithelial Neoplasia-Dependent p27^Kip1 Checkpoint Induces Senescence and Inhibits Cell Proliferation and Cancer Progression

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• 作者：Pradip K. Majumder ; Chiara Grisanzio ; Fionnuala O'Connell ; Marc Barry ; Joseph M. Brito ; Qing Xu ; Isil Guney ; Raanan Berger ; Paula Herman ; Rachel Bikoff ; Giuseppe Fedele ; Won-Ki Baek ; Shunyou Wang ; Katharine Ellwood-Yen ; Hong Wu ; Charles L. Sawyers ; Sabina Signoretti ; William C. Hahn ; Massimo Loda ; W
• 刊名：Cancer Cell
• 出版年：2008
• 出版时间：12 August 2008
• 年：2008
• 卷：14
• 期：2
• 页码：146-155
• 全文大小：1837 K

文摘

Summary

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.