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

作者：Majumder Pradip K; Grisanzio Chiara; O'Connell Fionnuala; Barry Marc; Brito Joseph M; Xu Qing; Guney Isil; Berger Raanan; Herman Paula; Bikoff Rachel; Fedele Giuseppe; Baek Won Ki; Wang Shunyou; Ellwood Yen Katharine; Wu Hong; Sawyers Charles L; Signoretti Sabina; Hahn William C; Loda Massimo^*; Sellers William R

来源：Cancer Cell, 2008, 14(2): 146-155.

DOI：10.1016/j.ccr.2008.06.002

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.

• 出版日期2008-8-12