Simon Hayward
Last active: 2/19/2015

Critical and distinct roles of p16 and telomerase in regulating the proliferative life span of normal human prostate epithelial progenitor cells.

Bhatia B, Jiang M, Suraneni M, Patrawala L, Badeaux M, Schneider-Broussard R, Multani AS, Jeter CR, Calhoun-Davis T, Hu L, Hu J, Tsavachidis S, Zhang W, Chang S, Hayward SW, Tang DG
J Biol Chem. 2008 283 (41): 27957-27972

PMID: 18662989 · PMCID: PMC2562067 · DOI:10.1074/jbc.M803467200

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.

MeSH Terms (14)

Antigens, Differentiation Cell Line Cell Proliferation Cellular Senescence Cyclin-Dependent Kinase Inhibitor p16 Epithelial Cells Humans Male Prostate Signal Transduction Stem Cells Telomerase Tumor Suppressor Protein p53 Up-Regulation

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