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Mol Cell Biol, July 1998, p. 3647-3658, Vol. 18, No. 7
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

RB and c-Myc Activate Expression of the E-Cadherin Gene in Epithelial Cells through Interaction with Transcription Factor AP-2

Eric Batsché,1 Christian Muchardt,2 Jürgen Behrens,3 Helen C. Hurst,4 and Chantal Crémisi1 *

CJF INSERM 94-02, Université René Descartes, 75270 Paris cedex 06,1 and Laboratoire des Virus Oncogènes, Institut Pasteur, Paris 75015,2 France; Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany3; and Gene Transcription Laboratory, Imperial Cancer Research Fund Oncology Unit, London W12 0NN, United Kingdom4

Received 19 December 1997/Returned for modification 26 January 1998/Accepted 13 April 1998

E-cadherin plays a pivotal role in the biogenesis of the first epithelium during development, and its down-regulation is associated with metastasis of carcinomas. We recently reported that inactivation of RB family proteins by simian virus 40 large T antigen (LT) in MDCK epithelial cells results in a mesenchymal conversion associated with invasiveness and a down-regulation of c-Myc. Reexpression of RB or c-Myc in such cells allows the reexpression of epithelial markers including E-cadherin. Here we show that both RB and c-Myc specifically activate transcription of the E-cadherin promoter in epithelial cells but not in NIH 3T3 mesenchymal cells. This transcriptional activity is mediated in both cases by the transcription factor AP-2. In vitro AP-2 and RB interaction involves the N-terminal domain of AP-2 and the oncoprotein binding domain and C-terminal domain of RB. In vivo physical interaction between RB and AP-2 was demonstrated in MDCK and HaCat cells. In LT-transformed MDCK cells, LT, RB, and AP-2 were all coimmunoprecipitated by each of the corresponding antibodies, and a mutation of the RB binding domain of the oncoprotein inhibited its binding to both RB and AP-2. Taken together, our results suggest that there is a tripartite complex between LT, RB, and AP-2 and that the physical and functional interactions between LT and AP-2 are mediated by RB. Moreover, they define RB and c-Myc as coactivators of AP-2 in epithelial cells and shed new light on the significance of the LT-RB complex, linking it to the dedifferentiation processes occurring during tumor progression. These data confirm the important role for RB and c-Myc in the maintenance of the epithelial phenotype and reveal a novel mechanism of gene activation by c-Myc.

* Corresponding author. Mailing address: CJF INSERM 94-02, Université René Descartes, 45 rue des Saints-Pères, 75270 Paris cedex 06, France. Phone: 33 1 42 86 20 77. Fax: 33 1 42 86 33 06.

Mol Cell Biol, July 1998, p. 3647-3658, Vol. 18, No. 7
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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