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- Title
Reexpression of the retinoblastoma protein in tumor cells induces senescence and telomerase inhibition.
- Authors
Xu, Hong-Ji; Zhou, Yunli; Ji, Wan; Perng, Guang-Shing; Kruzelock, Russell; Kong, Cheng-Te; Bast, Robert C; Mills, Gordon B; Li, Jian; Hu, Shi-Xue
- Abstract
Normal human diploid cells senesce in vitro and in vivo after a limited number of cell divisions. This process known as cellular senescence is an underlying cause of aging and a critical barrier for development of human cancers. We demonstrate here that reexpression of functional pRB alone in RB/p53-defective tumor cells via a modified tetracycline-regulated gene expression system resulted in a stable growth arrest at the G0/G1 phase of the cell cycle, preventing tumor cells from entering S phase in response to a variety of mitogenic stimuli. These cells displayed multiple morphological changes consistent with cellular senescence and expressed a senescence-associated β-galactosidase biomarker. Further studies indicated that telomerase activity, which was assumably essential for an extended proliferative life-span of neoplastic cells, was abrogated or repressed in the tumor cell lines after induction of pRB (but not p53) expression. Strikingly, when returned to an non-permissive medium for pRB expression, the pRB-induced senescent tumor cells resumed DNA synthesis, attempted to divide but most died in the process, a phenomenon similar to postsenescent crisis of SV40 T-antigen-transformed human diploid fibroblasts in late passage. These observations provide direct evidence that overexpression of pRB alone in RB/p53-defective tumor cells is sufficient to reverse their immortality and cause a phenotype that is, by all generally accepted criteria, indistinguishable from replicative senescence. The results suggest that pRB may play a causal role in the intrinsic cellular senescence program.
- Subjects
CELL division; AGING; CANCER cells; BIOMARKERS; DNA synthesis
- Publication
Oncogene, 1997, Vol 15, Issue 21, p2589
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/sj.onc.1201446