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 β-galactosidase. The induction of the premature senescence programme is mediated by inhibition of Cdk2 kinase activity, and p27KIP1 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.
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October 2003
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Research Article|
October 15 2003
Bcl-2 activates a programme of premature senescence in human carcinoma cells
Elvira CRESCENZI
;
Elvira CRESCENZI
∗Molecular Haematology and Cancer Biology Unit, Institute of Child Health, University College of London, 30 Guilford Street, London WC1N 1EH, U.K.
†Dipartimento di Biologia e Patologia Cellulare e Molecolare “L. Califano” and CEOS-CNR Facoltà di Medicina e Chirurgia, Università di Napoli “FEDERICO II”, Via Pansini 5, 80131, Naples, Italy
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Giuseppe PALUMBO
;
Giuseppe PALUMBO
†Dipartimento di Biologia e Patologia Cellulare e Molecolare “L. Califano” and CEOS-CNR Facoltà di Medicina e Chirurgia, Università di Napoli “FEDERICO II”, Via Pansini 5, 80131, Naples, Italy
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Hugh J. M. BRADY
Hugh J. M. BRADY
1
∗Molecular Haematology and Cancer Biology Unit, Institute of Child Health, University College of London, 30 Guilford Street, London WC1N 1EH, U.K.
1To whom correspondence should be sent (e-mail h.brady@ich.ucl.ac.uk).
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Biochem J (2003) 375 (2): 263–274.
Article history
Received:
June 12 2003
Revision Received:
July 17 2003
Accepted:
July 21 2003
Accepted Manuscript online:
July 21 2003
Citation
Elvira CRESCENZI, Giuseppe PALUMBO, Hugh J. M. BRADY; Bcl-2 activates a programme of premature senescence in human carcinoma cells. Biochem J 15 October 2003; 375 (2): 263–274. doi: https://doi.org/10.1042/bj20030868
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