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Cancer Resistance in Transgenic Mice Expressing the SAC Module of Par-4

Departments of ¹ Radiation Medicine, ² Pathology and Laboratory Medicine, ³ Microbiology, Immunology and Molecular Genetics; ⁴ Graduate Center for Toxicology; ⁵ Markey Cancer Center, University of Kentucky, Lexington, Kentucky and ⁶ Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska

Requests for reprints: Vivek M. Rangnekar, Department of Radiation Medicine, University of Kentucky, Room 309, Combs Research Building, 800 Rose Street, Lexington, KY 40536. Phone: 859-257-2677; Fax: 859-257-9608; E-mail: vmrang01{at}email.uky.edu.

Prostate apoptosis response-4 (Par-4) is a tumor-suppressor protein that induces apoptosis in cancer cells, but not in normal/immortalized cells. The cancer-specific proapoptotic action of Par-4 is encoded in its centrally located SAC domain. We report here the characterization of a novel mouse model with ubiquitous expression of the SAC domain. Although SAC transgenic mice displayed normal development and life span, they were resistant to the growth of spontaneous, as well as oncogene-induced, autochthonous tumors. Resistance to tumorigenesis was linked to inhibition of nuclear factor-B activity and induction of apoptosis by the SAC domain. Collectively, our findings provide genetic evidence that the SAC domain of Par-4 confers cancer resistance in transgenic mice without compromising normal viability or aging, and may have therapeutic significance. [Cancer Res 2007;67(19):9276–85]

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