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J. Biol. Chem., Vol. 278, Issue 51, 51408-51414, December 19, 2003

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Np63 Expression Is Regulated by the Phosphoinositide 3-Kinase Pathway^*

Christopher E. Barbieri, Christopher E. Barton, and Jennifer A. Pietenpol

From the Department of Biochemistry, Center in Molecular Toxicology, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee 37232

p63 is a homologue of p53 that functions to maintain progenitor cell populations in stratified epithelia. Np63 is overexpressed in epithelial cancers and has been shown to have oncogenic properties. We have previously reported that inhibition of epidermal growth factor receptor signaling results in a decrease in Np63 expression. Here, we demonstrate Np63 is a target of the phosphoinositide-3-kinase (PI3K) pathway downstream of the epidermal growth factor receptor. Treatment of keratinocytes with epidermal growth factor results in an increase in Np63 expression at the mRNA level, which is abrogated by inhibition of PI3K but not mitogen-activated protein kinase signaling. Small interfering RNA-mediated knockdown of the p110 catalytic subunit of PI3K results in a decrease in Np63 protein levels in keratinocytes. The results presented herein suggest that regulation of Np63 expression by the PI3K pathway plays a critical role in the survival and proliferative capacity of squamous epithelia.

Received for publication, September 8, 2003 , and in revised form, October 8, 2003.

^* This work was supported by National Institutes of Health Grant CA70856 (to J. A. P.), National Institutes of Health Training Grants GM073407 and CA009385 (to C. E. B.), and National Institutes of Health Grants ES00267 and CA68485 (Core services). 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.

To whom correspondence should be addressed: 652 PRB, Vanderbilt University Medical Center, Nashville, TN 37232. Tel.: 615-936-1512; Fax: 615-936-2294; E-mail: j.pietenpol{at}vanderbilt.edu.

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