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J. Biol. Chem., Vol. 283, Issue 41, 27957-27972, October 10, 2008

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Critical and Distinct Roles of p16 and Telomerase in Regulating the Proliferative Life Span of Normal Human Prostate Epithelial Progenitor Cells^*

Bobby Bhatia¹, Ming Jiang¹, Mahipal Suraneni, Lubna Patrawala², Mark Badeaux³, Robin Schneider-Broussard, Asha S. Multani^¶, Collene R. Jeter⁴, Tammy Calhoun-Davis, Limei Hu^||, Jianhua Hu^**, Spiridon Tsavachidis^**, Wei Zhang^||5, Sandy Chang^¶, Simon W. Hayward, and Dean G. Tang⁶

From the Department of Carcinogenesis, University of Texas M.D. Anderson Cancer Center, Science Park-Research Division, Smithville, Texas 78957, the Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee 37232, the Departments of ^¶Cancer Genetics, ^||Pathology, ^**Biostatistics, and Hematopathology, University of Texas M.D Anderson Cancer Center, Houston, Texas 77030, and the Program in Molecular Carcinogenesis, Graduate School of Biomedical Sciences, Houston, Texas 77030

Normal human prostate (NHP) epithelial cells undergo senescence in vitro and in vivo, but the underlying molecular mechanisms remain obscure. Here we show that the senescence of primary NHP cells, which are immunophenotyped as intermediate basal-like cells expressing progenitor cell markers CD44, 2β1, p63, hTERT, and CK5/CK18, involves loss of telomerase expression, up-regulation of p16, and activation of p53. Using genetically defined manipulations of these three signaling pathways, we show that p16 is the primary determinant of the NHP cell proliferative capacity and that hTERT is required for unlimited proliferative life span. Hence, suppression of p16 significantly extends NHP cell life span, but both p16 inhibition and hTERT are required to immortalize NHP cells. Importantly, immortalized NHP cells retain expression of most progenitor markers, demonstrate gene expression profiles characteristic of proliferating progenitor cells, and possess multilineage differentiation potential generating functional prostatic glands. Our studies shed important light on the molecular mechanisms regulating the proliferative life span of NHP progenitor cells.

Received for publication, May 7, 2008 , and in revised form, June 30, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants R01-AG023374, R01-ES015888, and R21-ES015893-01A1. This work was also supported by American Cancer Society Grant RSG MGO-105961, Department of Defense Grants W81XWH-07-1-0616 and PC073751, the Prostate Cancer Foundation, the Elsa Pardee Foundation (to D. G. T.), and two Center Grants, CCSG-5 P30 CA166672 and ES07784. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S12 and Tables S1 and S2.

¹ Both of these authors contributed equally to this work.

² Supported in part by a predoctoral fellowship from NIEHS, National Institutes of Health.

³ Supported in part by a predoctoral fellowship from the Department of Defense.

⁴ Supported in part by postdoctoral fellowships from the National Institutes of Health and American Urological Association.

⁵ Supported in part by CA-16672, Michael and Betty Kadoorie Foundation, Goodwin Fund, and M.D Anderson Cancer Center for Cancer Genomics Core Facility.

⁶ To whom correspondence should be addressed: Dept. of Carcinogenesis, University of Texas M.D. Anderson Cancer Center, Science Park-Research Division, P.O. Box 389, Smithville, TX 78957. Tel.: 512-237-9575; Fax: 512-237-2475; E-mail: dtang{at}mdanderson.org.

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