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Molecular and Cellular Biology, July 2005, p. 6154-6164, Vol. 25, No. 14
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.14.6154-6164.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

DNA-Binding and Transactivation Activities Are Essential for TAp63 Protein Degradation

Haoqiang Ying,1 Donny L. F. Chang,2 Hongwu Zheng,1 Frank McKeon,3 and Zhi-Xiong Jim Xiao1,2*

Department of Biochemistry,1 Department of Medicine, Boston University School of Medicine, 715 Albany St., Boston, Massachusetts 02118,2 Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 021153

Received 7 December 2004/ Returned for modification 13 January 2005/ Accepted 26 April 2005

The p53-related p63 gene encodes six isoforms with differing N and C termini. TAp63 isoforms possess a transactivation domain at the N terminus and are able to transactivate a set of genes, including some targets downstream of p53. Accumulating evidence indicates that TAp63 plays an important role in regulation of cell proliferation, differentiation, and apoptosis, whereas transactivation-inert {Delta}Np63 functions to inhibit p63 and other p53 family members. Mutations in the p63 gene that abolish p63 DNA-binding and transactivation activities cause human diseases, including ectrodactyly ectodermal dysplasia and facial clefting (EEC) syndrome. In this study, we show that mutant p63 proteins with a single amino acid substitution found in EEC syndrome are DNA binding deficient, transactivation inert, and highly stable. We demonstrate that TAp63 protein expression is tightly controlled by its specific DNA-binding and transactivation activities and that p63 is degraded in a proteasome-dependent, MDM2-independent pathway. In addition, the N-terminal transactivation domain of p63 is indispensable for its protein degradation. Furthermore, the wild-type TAp63{gamma} can act in trans to promote degradation of mutant TAp63{gamma} defective in DNA binding, and the TA domain deletion mutant of TAp63{gamma} inhibits transactivation activity and stabilizes the wild-type TAp63 protein. Taken together, these data suggest a feedback loop for p63 regulation, analogous to the p53-MDM2 feedback loop.

* Corresponding author. Mailing address: Department of Biochemistry, Boston University School of Medicine, K423, 715 Albany St., Boston, MA 02118. Phone: (617) 638-6011. Fax: (617) 638-5339. E-mail: jxiao{at}bu.edu.

Molecular and Cellular Biology, July 2005, p. 6154-6164, Vol. 25, No. 14
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.14.6154-6164.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • MacPartlin, M., Zeng, S. X., Lu, H. (2008). Phosphorylation and Stabilization of TAp63{gamma} by I{kappa}B Kinase-{beta}. J. Biol. Chem. 283: 15754-15761 [Abstract] [Full Text]  
  • Testoni, B., Mantovani, R. (2006). Mechanisms of transcriptional repression of cell-cycle G2/M promoters by p63. Nucleic Acids Res 34: 928-938 [Abstract] [Full Text]  


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