{Delta}Np63{alpha} and TAp63{alpha} Regulate Transcription of Genes with Distinct Biological Functions in Cancer and Development

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${Delta}$ Np63 ${alpha}$ and TAp63 ${alpha}$ Regulate Transcription of Genes with Distinct Biological Functions in Cancer and Development¹

Guojun Wu², Shuji Nomoto², Mohammad Obaidul Hoque², Tatiana Dracheva, Motonabu Osada, Chyi-Chia Richard Lee, Seung Myung Dong, Zhongmin Guo, Nicole Benoit, Yoram Cohen, Peggy Rechthand, Joseph Califano, Chul-so Moon, Edward Ratovitski, Jin Jen, David Sidransky³ and Barry Trink³

Departments of Otolaryngology-Head and Neck Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205-2196 [G. W., S. N., M. H., M. O., C-C. R. L., S. M. D., Z. G., N. B., Y. C., P. R., J. C., C. M., D. S., B. T.]; Laboratory of Population Genetics, National Cancer Institute, Rockville, Maryland [T. D., J. J.]; and Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205-2196 [E. R.]

The p63 gene shows remarkable structural similarity to the p53and p73 genes. Because of two promoters, the p63 gene generatestwo types of protein isoforms, TAp63 and ${Delta}$ Np63. Each type yieldsthree isotypes ( ${alpha}$ , ß, ${gamma}$ ) because of differential splicingof the p63 COOH terminus. The purpose of this study was to determinewhether there is a functional link between the distinct p63isotypes in their transcriptional regulation of downstream targetsand their role in various cellular functions. TAp63 ${alpha}$ and ${Delta}$ Np63 ${alpha}$ adenovirus expression vectors were introduced into Saos2 cellsfor 4 and 24 h, and then gene profiling was performed usinga DNA microarray chip analysis. Seventy-four genes (>2-foldchange in expression) were identified that overlapped betweentwo independent studies. Thirty-five genes were selected fordirect expression testing of which 27 were confirmed by reversetranscription-PCR or Northern blot analysis. A survey of thesegenes shows that p63 can regulate a wide range of downstreamgene targets with various cellular functions, including cellcycle control, stress, and signal transduction. Our study thusrevealed p63 transcriptional regulation of many genes in cancerand development while often demonstrating opposing regulatoryfunctions for TAp63 ${alpha}$ and ${Delta}$ Np63 ${alpha}$ .

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