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J. Biol. Chem., Vol. 282, Issue 1, 454-466, January 5, 2007

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Human TFDP3, a Novel DP Protein, Inhibits DNA Binding and Transactivation by E2F^*

Huan Qiao¹², Luisa Di Stefano¹³, Chan Tian, Yun-Yan Li, Yan-Hui Yin, Xiao-Ping Qian, Xue-Wen Pang, Yan Li, Michael Allen McNutt^¶, Kristian Helin⁴, Yu Zhang⁵, and Wei-Feng Chen⁶

From the Departments of Immunology and ^¶Pathology, Peking University Health Science Center, Beijing 100083, China and the Department of Experimental Oncology, European Institute of Oncology, 20141 Milan, Italy

The two known DP proteins, TFDP1 and -2, bind E2Fs to form heterodimers essential for high affinity DNA binding and efficient transcriptional activation/repression. Here we report the identification of a new member of the DP family, human TFDP3. Despite the high degree of sequence similarity, TFDP3 is apparently distinct from TFDP1 in function. Although TFDP3 retained the capacity to bind to E2F proteins, the resulting heterodimers failed to interact with the E2F consensus sequence. In contrast to the stimulatory effect of TFDP1, TFDP3 inhibited E2F-mediated transcriptional activation. Consistent with this observation, we found that ectopic expression of TFDP3 impaired cell cycle progression from G₁ to S phase instead of facilitating such a transition as TFDP1 does. Sequence substitution analysis indicated that the DNA binding domain of TFDP3 was primarily responsible for the lack of DNA binding ability of E2F-TFDP3 heterodimers and the inhibition of E2F-mediated transcriptional activation. Fine mapping further revealed four amino acids in this region, which were critical for the functional conversion from activation by TFDP1 to suppression by TFDP3. In conclusion, these studies identify a new DP protein and a novel mechanism whereby E2F function is regulated.

Received for publication, June 28, 2006 , and in revised form, August 28, 2006.

^* This work was supported by National Natural Science Foundation of China Grant 30531160045, National 863 Program in China Grant 2003AA215110, National Basic Research Program of China Grant 2006CB504300, and Beijing Natural Science Foundation Grant 7061003. 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 These two authors contributed equally to this work.

² Present address: Dept. of Medicine, Vanderbilt University School of Medicine, 2215 Garland Ave., 539 Light Hall, Nashville, TN 37232-0275.

³ Present address: Massachusetts General Hospital Cancer Center, Bldg. 149, 13th St., Charlestown, MA 02129.

⁴ Present address: BRIC, University of Copenhagen, Copenhagen 2100, Denmark.

⁵ To whom correspondence may be addressed: Dept. of Immunology, Peking University Health Science Center, 38 Xue Yuan Rd., Beijing 100083, China. Tel.: 86-10-82802593; Fax: 86-10-82801436; E-mail: zhangyu007{at}hsc.pku.edu.cn. ⁶ To whom correspondence may be addressed: Dept. of Immunology, Peking University Health Science Center, 38 Xue Yuan Rd., Beijing 100083, China. Tel.: 86-10-82802593; Fax: 86-10-82801436; E-mail: wfchen{at}public.bta.net.cn.

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