Bcl-2 activates a programme of premature senescence in human carcinoma cells

The apoptosis regulator Bcl-2 has been shown to modulate cell-cycle progression, favouring a quiescent state over a proliferative state, in both normal and tumour cells. We show here that constitutive expression of Bcl-2 in human carcinoma cells results in a cell-cycle arrest that within a few days...

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Bibliographic Details
Published in:Biochemical journal 2003-10, Vol.375 (Pt 2), p.263-274
Main Authors: Crescenzi, Elvira, Palumbo, Giuseppe, Brady, Hugh J M
Format: Article
Language:English
Subjects:
Apoptosis
Blotting, Western
Carcinoma - genetics
Carcinoma - metabolism
Carcinoma - pathology
CDC2-CDC28 Kinases - metabolism
Cell Cycle
Cell Cycle Proteins - metabolism
Cell Division
Cell Line, Tumor - drug effects
Cell Line, Tumor - metabolism
Cellular Senescence
Cyclin-Dependent Kinase 2
Cyclin-Dependent Kinase Inhibitor p27
Doxycycline - pharmacology
Humans
Phenotype
Proto-Oncogene Proteins c-bcl-2 - genetics
Proto-Oncogene Proteins c-bcl-2 - metabolism
Transfection
Tumor Suppressor Proteins - metabolism
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Summary:The apoptosis regulator Bcl-2 has been shown to modulate cell-cycle progression, favouring a quiescent state over a proliferative state, in both normal and tumour cells. We show here that constitutive expression of Bcl-2 in human carcinoma cells results in a cell-cycle arrest that within a few days can become irreversible. Arrested cells acquire a senescent-like phenotype, which consists of several characteristic morphological alterations and increased activity of senescence-associated beta-galactosidase. The induction of the premature senescence programme is mediated by inhibition of Cdk2 kinase activity, and p27(KIP1) is required to maintain the senescent phenotype. We propose that the ability to activate an endogenous premature senescence programme allows Bcl-2 to suppress tumour growth. These results suggest that the down-regulation of Bcl-2 expression, which has been observed during the development and progression of human carcinoma, is related to the ability of Bcl-2 to severely hamper the growth of carcinoma cells and to induce a permanent cell-cycle arrest, with the features of senescence.
ISSN:0264-6021
1470-8728
DOI:10.1042/BJ20030868