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J. Biol. Chem., Vol. 282, Issue 41, 30216-30226, October 12, 2007

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Carboxyl-terminal Proteolytic Processing of CUX1 by a Caspase Enables Transcriptional Activation in Proliferating Cells^*

Mary Truscott¹, Jean-Bernard Denault^¶, Brigitte Goulet, Lam Leduy, Guy S. Salvesen^¶, and Alain Nepveu^||**2

From the Molecular Oncology Group, McGill University Health Center, Montreal, Quebec H3A 1A1, Canada, the Departments of Biochemistry, ^||Medicine, and ^**Oncology, McGill University, Montreal, Quebec H3A 1A1, Canada, and the ^¶Program in Apoptosis and Cell Death Research, The Burnham Institute, La Jolla, California 92037

Proteolytic processing at the end of the G₁ phase generates a CUX1 isoform, p110, which functions either as a transcriptional activator or repressor and can accelerate entry into S phase. Here we describe a second proteolytic event that generates an isoform lacking two active repression domains in the COOH terminus. This processing event was inhibited by treatment of cells with synthetic and natural caspase inhibitors. In vitro, several caspases generated a processed isoform that co-migrated with the in vivo generated product. In cells, recombinant CUX1 proteins in which the region of cleavage was deleted or in which Asp residues were mutated to Ala, were not proteolytically processed. Importantly, this processing event was not associated with apoptosis, as assessed by terminal dUTP nick end labeling assay, cytochrome c localization, poly(ADP-ribose) polymerase cleavage, and fluorescence-activated cell sorting. Moreover, processing was observed in S phase but not in early G₁, suggesting that it is regulated through the cell cycle. The functional importance of this processing event was revealed in reporter and cell cycle assays. A recombinant, processed, CUX1 protein was a more potent transcriptional activator of several cell cycle-related genes and was able to accelerate entry into S phase, whereas mutants that could not be processed were inactive in either assay. Conversely, cells treated with the quinoline-Val Asp-2,6-difluorophenoxymethylketone caspase inhibitor proliferated more slowly and exhibited delayed S phase entry following exit from quiescence. Together, our results identify a substrate of caspases in proliferating cells and suggest a mechanism by which caspases can accelerate cell cycle progression.

Received for publication, March 19, 2007 , and in revised form, August 3, 2007.

^* This research was supported by Canadian Institute of Health Research Grant MOP-11590 and by Canadian Cancer Society Grant 014288 (to A. N.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Recipient of a studentship from the Terry Fox Foundation through the National Cancer Institute of Canada during the initial stages of this study and a studentship from the Fonds de Recherches en Santé Québec during the latter part of the study.

² Recipient of a scholarship from the Fonds de la Recherche en Santé du Québec. To whom correspondence should be addressed: McGill University Health Center, 687 Pine Ave. W., Montreal, Quebec H3A 1A1, Canada. Tel.: 514-934-1934 (ext. 35842); Fax: 514-843-1478; E-mail: alain.nepveu{at}mcgill.ca.

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