Critical and distinct roles of p16 and telomerase in regulating the proliferative life span of normal human prostate epithelial progenitor cells.
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, alpha2beta1, 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.
Bhatia
Bobby
B
Department of Carcinogenesis, University of Texas M.D. Anderson Cancer Center, Science Park-Research Division, Smithville, Texas 78957.
Jiang
Ming
M
Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee 37232, the Departments of.
Suraneni
Mahipal
M
Department of Carcinogenesis, University of Texas M.D. Anderson Cancer Center, Science Park-Research Division, Smithville, Texas 78957.
Patrawala
Lubna
L
Department of Carcinogenesis, University of Texas M.D. Anderson Cancer Center, Science Park-Research Division, Smithville, Texas 78957.
Badeaux
Mark
M
Department of Carcinogenesis, University of Texas M.D. Anderson Cancer Center, Science Park-Research Division, Smithville, Texas 78957.
Schneider-Broussard
Robin
R
Department of Carcinogenesis, University of Texas M.D. Anderson Cancer Center, Science Park-Research Division, Smithville, Texas 78957.
Multani
Asha S
AS
Cancer Genetics, University of Texas M.D Anderson Cancer Center, Houston, Texas 77030.
Jeter
Collene R
CR
Department of Carcinogenesis, University of Texas M.D. Anderson Cancer Center, Science Park-Research Division, Smithville, Texas 78957.
Calhoun-Davis
Tammy
T
Department of Carcinogenesis, University of Texas M.D. Anderson Cancer Center, Science Park-Research Division, Smithville, Texas 78957.
Hu
Limei
L
Pathology, University of Texas M.D Anderson Cancer Center, Houston, Texas 77030.
Hu
Jianhua
J
Biostatistics, University of Texas M.D Anderson Cancer Center, Houston, Texas 77030.
Tsavachidis
Spiridon
S
Biostatistics, University of Texas M.D Anderson Cancer Center, Houston, Texas 77030.
Zhang
Wei
W
Pathology, University of Texas M.D Anderson Cancer Center, Houston, Texas 77030.
Chang
Sandy
S
Cancer Genetics, University of Texas M.D Anderson Cancer Center, Houston, Texas 77030; Hematopathology, University of Texas M.D Anderson Cancer Center, Houston, Texas 77030.
Hayward
Simon W
SW
Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee 37232, the Departments of.
Tang
Dean G
DG
Department of Carcinogenesis, University of Texas M.D. Anderson Cancer Center, Science Park-Research Division, Smithville, Texas 78957; Program in Molecular Carcinogenesis, Graduate School of Biomedical Sciences, Houston, Texas 77030. Electronic address: dtang@mdanderson.org.
D000943:Antigens, Differentiation / Q000096:biosynthesis; D002460:Cell Line; D049109:Cell Proliferation; D016922:Cellular Senescence / Q000502:physiology*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D008297:Male; D011467:Prostate / Q000166:cytology / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D019098:Telomerase / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D015854:Up-Regulation / Q000502:physiology
D000943:Antigens, Differentiation; D019941:Cyclin-Dependent Kinase Inhibitor p16; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C509186:TERT protein, human; D019098:Telomerase