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Molecular and Cellular Biology, November 2007, p. 7703-7717, Vol. 27, No. 21
0270-7306/07/$08.00+0     doi:10.1128/MCB.01991-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

E-Cadherin Is Required for Caveolin-1-Mediated Down-Regulation of the Inhibitor of Apoptosis Protein Survivin via Reduced ß-Catenin-Tcf/Lef-Dependent Transcription{triangledown} ,{ddagger}

Vicente A. Torres ,{dagger} Julio C. Tapia,{dagger} Diego A. Rodriguez, Alvaro Lladser, Cristian Arredondo, Lisette Leyton, and Andrew F. G. Quest*

Laboratory of Cellular Communication, FONDAP Center for Molecular Studies of the Cell (CEMC), Facultad de Medicina, Universidad de Chile, Santiago, Chile

Received 24 October 2006/ Returned for modification 5 January 2007/ Accepted 16 August 2007

Caveolin-1 reportedly acts as a tumor suppressor and promotes events associated with tumor progression, including metastasis. The molecular mechanisms underlying such radical differences in function are not understood. Recently, we showed that caveolin-1 inhibits expression of the inhibitor of apoptosis protein survivin via a transcriptional mechanism involving the ß-catenin-Tcf/Lef pathway. Surprisingly, while caveolin-1 expression decreased survivin mRNA and protein levels in HT29(ATCC) human colon cancer cells, this was not the case in metastatic HT29(US) cells. Survivin down-regulation was paralleled by coimmunoprecipitation and colocalization of caveolin-1 with ß-catenin in HT29(ATCC) but not HT29(US) cells. Unlike HT29(ATCC) cells, HT29(US) cells expressed small amounts of E-cadherin that accumulated in intracellular patches rather than at the cell surface. Re-expression of E-cadherin in HT29(US) cells restored the ability of caveolin-1 to down-regulate ß-catenin-Tcf/Lef-dependent transcription and survivin expression, as seen in HT29(ATCC) cells. In addition, coimmunoprecipitation and colocalization between caveolin-1 and ß-catenin increased upon E-cadherin expression in HT29(US) cells. In human embryonic kidney HEK293T and HT29(US) cells, caveolin-1 and E-cadherin cooperated in suppressing ß-catenin-Tcf/Lef-dependent transcription as well as survivin expression. Finally, mouse melanoma B16-F10 cells, another metastatic cell model with low endogenous caveolin-1 and E-cadherin levels, were characterized. In these cells, caveolin-1-mediated down-regulation of survivin in the presence of E-cadherin coincided with increased apoptosis. Thus, the absence of E-cadherin severely compromises the ability of caveolin-1 to develop activities potentially relevant to its role as a tumor suppressor.

* Corresponding author. Mailing address: FONDAP Center for Molecular Studies of the Cell (CEMC), Facultad de Medicina, Universidad de Chile, Av. Independencia 1027, Santiago, Chile. Phone and fax: (562) 738-2015. E-mail: aquest{at}med.uchile.cl

{triangledown} Published ahead of print on 4 September 2007.

{ddagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{dagger} These authors contributed equally to this work.

Molecular and Cellular Biology, November 2007, p. 7703-7717, Vol. 27, No. 21
0270-7306/07/$08.00+0     doi:10.1128/MCB.01991-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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