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Molecular and Cellular Biology, April 2003, p. 2264-2276, Vol. 23, No. 7
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.7.2264-2276.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

The {Delta}Np63{alpha} Phosphoprotein Binds the p21 and 14-3-3{sigma} Promoters In Vivo and Has Transcriptional Repressor Activity That Is Reduced by Hay-Wells Syndrome-Derived Mutations

Matthew D. Westfall, Deborah J. Mays, Joseph C. Sniezek,{dagger} and Jennifer A. Pietenpol*

Department of Biochemistry, Center in Molecular Toxicology, The Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232,

Received 17 July 2002/ Returned for modification 21 August 2002/ Accepted 2 January 2003

p63 is a recently identified homolog of p53 that is found in the basal layer of several stratified epithelial tissues such as the epidermis, oral mucosa, prostate, and urogenital tract. Studies with p63-/- mice and analysis of several human autosomal-dominant disorders with germ line p63 mutations suggest p63 involvement in maintaining epidermal stem cell populations. The p63 gene encodes six splice variants with reported transactivating or dominant-negative activities. The goals of the current study were to determine the splice variants that are expressed in primary human epidermal keratinocytes (HEKs) and the biochemical activity p63 has in these epithelial cell populations. We found that the predominant splice variant expressed in HEKs was {Delta}Np63{alpha}, and it was present as a phosphorylated protein. During HEK differentiation, {Delta}Np63{alpha} and p53 levels decreased, while expression of p53 target genes p21 and 14-3-3{sigma} increased. {Delta}Np63{alpha} had transcriptional repressor activity in vitro, and this activity was reduced in {Delta}Np63{alpha} proteins containing point mutations, corresponding to those found in patients with Hay-Wells syndrome. Further, we show that {Delta}Np63{alpha} and p53 can bind the p21 and 14-3-3{sigma} promoters in vitro and in vivo, with decreased binding of p63 to these promoters during HEK differentiation. These data suggest that {Delta}Np63{alpha} acts as a transcriptional repressor at select growth regulatory gene promoters in HEKs, and this repression likely plays an important role in the proliferative capacity of basal keratinocytes.

* Corresponding author. Mailing address: 652 Medical Research Building II, The Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232-6838. Phone: (615) 936-1512. Fax: (615) 936-2294. E-mail: jennifer.pietenpol{at}vanderbilt.edu.

{dagger} Present address: Head and Neck Oncologic Surgery, MCHK-DSH, Tripler Army Medical Center, Honolulu, HI 96859.

Molecular and Cellular Biology, April 2003, p. 2264-2276, Vol. 23, No. 7
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.7.2264-2276.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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