Identification of PHLPP1 as a Tumor Suppressor Reveals the Role of Feedback Activation in PTEN-Mutant Prostate Cancer Progression

被引：145

作者：

Chen, Muhan ^{[1
]}

Pratt, Christopher P. ^{[1
]}

Zeeman, Martha E. ^{[1
]}

Schultz, Nikolaus ^{[2
]}

Taylor, Barry S. ^{[2
]}

O'Neill, Audrey ^{[3
]}

Castillo-Martin, Mireia ^{[4
]}

Nowak, Dawid G. ^{[1
]}

Naguib, Adam ^{[1
]}

Grace, Danielle M. ^{[1
]}

Murn, Jernej ^{[1
]}

Navin, Nick ^{[5
]}

Atwal, Gurinder S. ^{[1
]}

Sander, Chris ^{[2
]}

Gerald, William L. ^{[6
]}

Cordon-Cardo, Carlos ^{[4
]}

Newton, Alexandra C. ^{[3
]}

Carver, Brett S. ^{[7
]}

Trotman, Lloyd C. ^{[1
]}

机构：

[1] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA

[2] Mem Sloan Kettering Canc Ctr, Computat Biol Program, New York, NY 10021 USA

[3] Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USA

[4] Columbia Univ, Dept Pathol, New York, NY 10032 USA

[5] Univ Texas MD Anderson Canc Ctr, Dept Genet, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA

[6] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, Dept Pathol, New York, NY 10021 USA

[7] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, Div Urol, Dept Surg, New York, NY 10021 USA

来源：

CANCER CELL | 2011年 / 20卷 / 02期

关键词：

MTOR COMPLEX; MICE; AKT; PHOSPHATASE; SENESCENCE; PATHWAY; PROTEIN; GROWTH; DEPHOSPHORYLATES; TUMORIGENESIS;

D O I：

10.1016/j.ccr.2011.07.013

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Hyperactivation of the PI 3-kinase/AKT pathway is a driving force of many cancers. Here we identify the AKT-inactivating phosphatase PHLPP1 as a prostate tumor suppressor. We show that Phlpp1-loss causes neoplasia and, on partial Pten-loss, carcinoma in mouse prostate. This genetic setting initially triggers a growth suppressive response via p53 and the Phlpp2 ortholog, and reveals spontaneous Trp53 inactivation as a condition for full-blown disease. Surprisingly, the codeletion of PTEN and PHLPP1 in patient samples is highly restricted to metastatic disease and tightly correlated to deletion of TP53 and PHLPP2. These data establish a conceptual framework for progression of PTEN mutant prostate cancer to life-threatening disease.

引用

页码：173 / 186

页数：14

共 42 条

[11] SENESCENCE Senescence in tumours: evidence from mice and humans [J].

Collado, Manuel ;

Serrano, Manuel .

NATURE REVIEWS CANCER, 2010, 10 (01) :51-57

[12] Impaired Fas response and autoimmunity in Pten+/- mice [J].

Di Cristofano, A ;

Kotsi, P ;

Peng, YF ;

Cordon-Cardo, C ;

Elkon, KB ;

Pandolfi, PP .

SCIENCE, 1999, 285 (5436) :2122-2125

[13] Pten and p27KIP1 cooperate in prostate cancer tumor suppression in the mouse [J].

Di Cristofano, A ;

De Acetis, M ;

Koff, A ;

Cordon-Cardo, C ;

Pandolfi, PP .

NATURE GENETICS, 2001, 27 (02) :222-224

[14] SMAD4-dependent barrier constrains prostate cancer growth and metastatic progression [J].

Ding, Zhihu ;

Wu, Chang-Jiun ;

Chu, Gerald C. ;

Xiao, Yonghong ;

Ho, Dennis ;

Zhang, Jingfang ;

Perry, Samuel R. ;

Labrot, Emma S. ;

Wu, Xiaoqiu ;

Lis, Rosina ;

Hoshida, Yujin ;

Hiller, David ;

Hu, Baoli ;

Jiang, Shan ;

Zheng, Hongwu ;

Stegh, Alexander H. ;

Scott, Kenneth L. ;

Signoretti, Sabina ;

Bardeesy, Nabeel ;

Wang, Y. Alan ;

Hill, David E. ;

Golub, Todd R. ;

Stampfer, Meir J. ;

Wong, Wing H. ;

Loda, Massimo ;

Mucci, Lorelei ;

Chin, Lynda ;

DePinho, Ronald A. .

NATURE, 2011, 470 (7333) :269-+

[15] Maximizing mouse cancer models [J].

Frese, Kristopher K. ;

Tuveson, David A. .

NATURE REVIEWS CANCER, 2007, 7 (09) :645-658

[16] The phosphatase PHLPP controls the cellular levels of protein kinase C [J].

Gao, Tianyan ;

Brognard, John ;

Newton, Alexandra C. .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2008, 283 (10) :6300-6311

[17] PHLPP: A phosphatase that directly dephosphorylates akt, promotes apoptosis, and suppresses tumor growth [J].

Gao, TY ;

Furnari, F ;

Newton, AC .

MOLECULAR CELL, 2005, 18 (01) :13-24

[18] The Pharmacology of mTOR Inhibition [J].

Guertin, David A. ;

Sabatini, David M. .

SCIENCE SIGNALING, 2009, 2 (67) :pe24

[19] mTOR Complex 2 Is Required for the Development of Prostate Cancer Induced by Pten Loss in Mice [J].

Guertin, David A. ;

Stevens, Deanna M. ;

Saitoh, Maki ;

Kinkel, Stephanie ;

Crosby, Katherine ;

Sheen, Joon-Ho ;

Mullholland, David J. ;

Magnuson, Mark A. ;

Wu, Hong ;

Sabatini, David M. .

CANCER CELL, 2009, 15 (02) :148-159

[20] Activation of p53-dependent growth suppression in human cells by mutations in PTEN or PIK3CA [J].

Kim, Jung-Sik ;

Lee, Carolyn ;

Bonifant, Challice L. ;

Ressom, Habtom ;

Waldman, Todd .

MOLECULAR AND CELLULAR BIOLOGY, 2007, 27 (02) :662-677

← 1 2 3 4 5 →