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J. Biol. Chem., Vol. 280, Issue 20, 20111-20119, May 20, 2005

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The C-terminal Sterile Motif and the Extreme C Terminus Regulate the Transcriptional Activity of the Isoform of p73^*

Gang Liu and Xinbin Chen

From the Department of Cell Biology, The University of Alabama, Birmingham, Alabama 35294

p73, a member of the p53 family, is expressed from two separate promoters, generating TA and N variants. Each variant potentially encodes at least seven alternatively spliced isoforms (–). Interestingly, we and others have shown that the isoform of p73 has a weaker transcriptional activity than the isoform. Because the isoform has an extended C terminus consisting of a sterile motif (SAM) and an extreme C terminus, it appears that the C terminus is inhibitory. However, how the C terminus inhibits the transcriptional activity of p73 has not been determined. Here, we found that both the SAM and the extreme C terminus exert their inhibitory activity by preventing the accessibility of p300/CBP to the activation domain in p73. Specifically, we showed that the SAM and the extreme C terminus together or individually are capable of repressing the function of p73 activation domain, but neither interacts directly with the activation domain, or suppresses the DNA-binding activity, of the p73 protein. We also showed that the intact state of the SAM and the extreme C terminus is essential for their inhibitory functions such that a small deletion of either the SAM or the extreme C terminus abolishes its inhibitory activity. Furthermore, we showed that both inhibitory domains in the C terminus are capable of suppressing the function of a cis heterologous activation domain from p53 or Gal4. Finally, we showed that both inhibitory domains suppress the ability of p73 to interact with the transcriptional coactivators p300/CBP that are necessary for the initiation of transcription.

Received for publication, December 9, 2004 , and in revised form, February 25, 2005.

^* This work was supported by NCI, National Institutes of Health Grant CA081237 and by the Department of Defense Prostate Cancer Research Program under award W81XWH-04-1-0079. 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.

To whom correspondence should be addressed: Dept. of Cell Biology, The University of Alabama at Birmingham, MCLM 660, 1918 University Blvd., Birmingham, AL 35294-0005. Tel.: 205-975-1798; Fax: 205-934-0950; E-mail: xchen{at}uab.edu.

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