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Molecular and Cellular Biology, July 2005, p. 6077-6089, Vol. 25, No. 14
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.14.6077-6089.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Differential Recognition of Response Elements Determines Target Gene Specificity for p53 and p63

Motonobu Osada,1 Hannah Lui Park,1 Yuichi Nagakawa,2 Keishi Yamashita,1 Alexey Fomenkov,3 Myoung Sook Kim,1 Guojun Wu,1 Shuji Nomoto,1 Barry Trink,1* and David Sidransky1*

Department of Otolaryngology, Division of Head and Neck Surgery,1 Department of Surgery,2 Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland 212053

Received 7 October 2004/ Returned for modification 7 December 2004/ Accepted 7 April 2005

p63 is a member of the p53 tumor suppressor gene family, which regulates downstream target gene expression by binding to sequence-specific response elements similar to those of p53. By using oligonucleotide expression microarray analysis and analyzing the promoters of p63-induced genes, we have identified novel p63-specific response elements (p63-REs) in the promoter regions of EVPL and SMARCD3. These p63-REs exhibit characteristic differences from the canonical p53-RE (RRRCWWGYYY) in both the core-binding element (CWWG) as well as the RRR and/or YYY stretches. Luciferase assays on mutagenized promoter constructs followed by electromobility shift analysis showed that p53 preferentially activates and binds to the RRRCATGYYY sequence, whereas p63 preferentially activates RRRCGTGYYY. Whereas EVPL protein is highly expressed in epithelial cells of the skin and pharynx in the p63+/+ mouse, it is undetectable in these tissues in the p63–/– mouse. Our results indicate that p63 can regulate expression of specific target genes such as those involved in skin, limb, and craniofacial development by preferentially activating distinct p63-specific response elements.

* Corresponding author. Mailing address: Department of Otolaryngology, Division of Head and Neck Surgery, Johns Hopkins University School of Medicine, 818 Ross Research Building, 720 Rutland Avenue, Baltimore, MD 21205. Phone: (410) 502-5153. Fax: (410) 614-1411. E-mail for Barry Trink: btrink{at}jhmi.edu. E-mail for David Sidransky: dsidrans{at}jhmi.edu.

Molecular and Cellular Biology, July 2005, p. 6077-6089, Vol. 25, No. 14
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.14.6077-6089.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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