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Targeted Ablation of Par-4 Reveals a Cell Type–Specific Susceptibility to Apoptosis-Inducing Agents

¹ Department of Pathology, Harvard Medical School, Boston, Massachusetts; ² Department of Biomedical Sciences, Cornell University, Ithaca, New York; and ³ Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts

Requests for reprints: Yang Shi, Department of Pathology, Harvard Medical School, 77 Louis Pasteur Avenue, NRB854b, Boston, MA 02115. Phone: 617-432-4318; Fax: 617-432-6687; E-mail: yang_shi{at}hms.harvard.edu.

The prostate apoptosis response-4 (Par-4) protein has been shown to function as an effector of cell death in response to various apoptotic stimuli, and down-regulation of this protein has been suggested to be a key event during tumorigenesis. Several studies suggest an essential function for the COOH-terminal leucine repeats/death domain of Par-4 in mediating apoptosis. We investigated the biological role of this domain in vivo by generating knock-out mice expressing a Par-4 mutant protein lacking the COOH terminus domain. We found that the Par-4 mutant mice are viable and fertile with no overt phenotype, thus excluding an essential role for the COOH terminus domain of Par-4 in embryogenesis and developmental apoptosis. To determine the requirement of Par-4 for apoptosis, we treated primary fibroblasts with various stimuli that trigger mitochondria and membrane receptor cell death pathways. Fibroblasts isolated from Par-4 mutant mice are as sensitive as the wild-type cells to these apoptosis-inducing agents. Similar effects were observed following RNA interference (RNAi)–mediated knockdown of Par-4 in these cells. In contrast, RNAi-mediated depletion of Par-4 in HeLa cells resulted in a significant inhibition of apoptosis induced by various proapoptotic agents. Taken together, our findings provide strong genetic evidence that the proapoptotic function of Par-4 is dependent on the cellular context and raise the possibility that alterations of Par-4 function may occur during carcinogenesis. (Cancer Res 2006; 66(7): 3456-62)

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