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J. Biol. Chem., Vol. 281, Issue 15, 10473-10481, April 14, 2006

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Activating Transcription Factor 3, a Stress-inducible Gene, Suppresses Ras-stimulated Tumorigenesis^*

From the Ohio State Biochemistry Program, Department of Molecular and Cellular Biochemistry and Center for Molecular Neurobiology, Ohio State University, Columbus, Ohio 43210

ATF3 is a stress-inducible gene that encodes a member of the ATF/CREB family of transcription factors. Current literature indicates that ATF3 affects cell death and cell cycle progression. However, controversies exist, because it has been demonstrated to be a negative or positive regulator of these processes. We sought to study the roles of ATF3 in both cell death and cell cycle regulation in the same cell type using mouse fibroblasts. We show that ATF3 promotes apoptosis and cell cycle arrest. Fibroblasts deficient in ATF3 (ATF3^-/-) were partially protected from UV-induced apoptosis, and fibroblasts ectopically expressing ATF3^-/- under the tet-off system exhibited features characteristic of apoptosis upon ATF3 induction. Furthermore, ATF3^-/- fibroblasts transitioned from G₂ to S phase more efficiently than the ATF3^+/+ fibroblasts, suggesting a growth arrest role of ATF3. Consistent with the growth arrest and pro-apoptotic roles of ATF3, ATF3^- fibroblasts upon Ras transformation exhibited higher growth rate, produced more colonies in soft agar, and formed larger tumor upon xenograft injection than the ATF3^+/+ counterparts. ATF3^-/- cells, either with or without Ras transformation, had increased Rb phosphorylation and higher levels of various cyclins. Significantly, ATF3 bound to the cyclin D1 promoter as shown by chromatin immunoprecipitation (ChIP) assay and repressed its transcription by a transcription assay. Taken together, our results indicate that ATF3 promotes cell death and cell arrest, and suppresses Ras-mediated tumorigenesis. Potential explanations for the controversy about the roles of ATF3 in cell cycle and cell death are discussed.

Received for publication, August 23, 2005 , and in revised form, December 21, 2005.

^* This work was supported by Grant DK59605 (to T. H.) from the National Institutes of Health and Grant 7-05-RA-52 (to T. H.) from the American Diabetes Association. 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 Current address: Vanda Pharmaceuticals, Inc., 9620 Medical Center Dr., Suite 201, Rockville, MD 20850.

² To whom correspondence should be addressed: Rm. 174 Rightmire Hall, 1060 Carmack Rd., Ohio State University, Columbus, OH 43210. Tel.: 614-292-2910; Fax: 614-292-5379; E-mail: hai.2{at}osu.edu.

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