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J. Biol. Chem., Vol. 281, Issue 5, 2533-2542, February 3, 2006

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The Unique NH₂-terminally Deleted (N) Residues, the PXXP Motif, and the PPXY Motif Are Required for the Transcriptional Activity of the N Variant of p63^*

From the Department of Cell Biology, University of Alabama at Birmingham, Birmingham, Alabama 35294-0005

p63, a member of the p53 family of transcription factors, is known to be involved in epithelial development. However, its role in tumorigenesis is unclear. Contributing to this uncertainty, the TP63 locus can express multiple gene products from two different promoters. Utilization of the upstream promoter results in expression of the TAp63 variant with an activation domain similar to p53. In contrast, the NH₂-terminally deleted (N) p63 variant, transcribed from a cryptic promoter in intron 3, lacks such an activation domain. Thus, the TAp63 and Np63 variants possess a wide ranging ability to up-regulate p53 target genes. Consequentially, the disparity in transactivation potential between p63 variants has given rise to the hypothesis that the Np63 variant can serve as oncoprotein by opposing the activity of the TAp63 variant and p53. However, recent studies have revealed a transcriptional activity for Np63. This study was undertaken to address the transcriptional activity of the Np63 variant. Here, we showed that all NH₂-terminally deleted p63 isoforms retain a potential in transactivation and growth suppression. Interestingly, Np63 possesses a remarkable ability to suppress cell proliferation and transactivate target genes, which is consistently higher than that seen with Np63. In contrast, Np63 has a weak or undetectable activity dependent upon the cell lines used. We also demonstrate that an intact DNA-binding domain is required for Np63 function. In addition, we found that the novel activation domain for the Np63 variant is composed of the 14 unique N residues along with the adjacent region, including a PXXP motif. Finally, we demonstrated that a PPXY motif shared by Np63 and Np63 is required for optimal transactivation of target gene promoters, suggesting that the PPXY motif is requisite for Np63 function.

Received for publication, July 21, 2005 , and in revised form, November 29, 2005.

^* This work is supported in part by National Institutes of Health Grant RO1 CA102188. 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 To whom correspondence should be addressed: MCLM 660, 1530 3rd Ave. S., Birmingham, AL 35294-0005. Tel.: 205-975-1798; Fax: 205-934-0950; E-mail: xchen{at}uab.edu.

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