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Molecular and Cellular Biology, November 2002, p. 7877-7888, Vol. 22, No. 22
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.22.7877-7888.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

The Retinoblastoma Protein Binds the Promoter of the Survival Gene bcl-2 and Regulates Its Transcription in Epithelial Cells through Transcription Factor AP-2

Stephanie Decary,1 Julien T. Decesse,1 Vasily Ogryzko,1 John C. Reed,2 Irina Naguibneva,1 Annick Harel-Bellan,1 and Chantal E. Cremisi1*

Laboratoire Oncogenese, Differenciation et Transduction du Signal, CNRS UPR 9079, Institut Andre Lwoff, 94801 Villejuif, France,1 The Burnham Institute, La JollaCalifornia 920372

Received 22 April 2002/ Returned for modification 7 June 2002/ Accepted 5 August 2002

The retinoblastoma (RB) gene product has been shown to restrict cell proliferation, promote cell differentiation, and inhibit apoptosis. Loss of RB function can induce both p53-dependent apoptosis and p53-independent apoptosis; little is known about the mechanisms of RB-regulated p53-independent apoptosis. Here we show that RB specifically activates transcription of the survival gene bcl-2 in epithelial cells but not in NIH 3T3 mesenchymal cells. This transcriptional activity is mediated by the transcription factor AP-2. By monitoring protein-DNA interactions in living cells using formaldehyde cross-linking and chromatin immunoprecipitation, we show that endogenous RB and AP-2 both bind to the same bcl-2 promoter sequence. In addition, we demonstrate that RB and AP-2 also bind to the E-cadherin gene promoter in vivo, consistent with regulation of this promoter by both AP-2 and RB in epithelial cells. This study provides evidence that RB activates bcl-2 and E-cadherin by binding directly to the respective promoter sequences and not indirectly by repressing an inhibitor. This recruitment is mediated by a transcription factor, in this case AP-2. For the first time, our results suggest a direct molecular mechanism by which RB might inhibit apoptosis independently of p53. The results are discussed in a context where RB and Bcl-2 contribute under nonpathological conditions to the maintenance of cell viability in association with a differentiated phenotype, contributing to the tumor suppressor function of RB and playing important roles in normal development.

* Corresponding author. Mailing address: Laboratoire Oncogenese, Differenciation et Transduction du Signal, CNRS UPR 9079, Institut Andre Lwoff, 7 Rue Guy Moquet, 94801 Villejuif, France. Phone: 33 1 49 58 33 27. Fax: 33 1 49 58 33 32. E-mail: cremisi{at}vjf.cnrs.fr.

Molecular and Cellular Biology, November 2002, p. 7877-7888, Vol. 22, No. 22
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.22.7877-7888.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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