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J. Biol. Chem., Vol. 281, Issue 47, 36162-36172, November 24, 2006

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Apigenin Inhibition of Involucrin Gene Expression Is Associated with a Specific Reduction in Phosphorylation of Protein Kinase C Tyr^311*

Sivaprakasam Balasubramanian, Ling Zhu, and Richard L. Eckert^¶||**1

From the Departments of Physiology and Biophysics, Dermatology, ^¶Biochemistry, ^||Reproductive Biology, and ^**Oncology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106-4970

Apigenin is a plant-derived flavanoid that has significant promise as a skin cancer chemopreventive agent. In the present study, we examine the mechanism whereby apigenin regulates normal human keratinocyte differentiation. Expression of involucrin (hINV), a marker of keratinocyte differentiation, is increased by differentiating agents via a protein kinase C (PKC), Ras, MEKK1, MEK3 cascade that increases AP1 factor level and AP1 factor binding to DNA elements in the hINV promoter. We show that apigenin inhibits this response. Apigenin suppresses the 12-O-tetradeconylphorbol-13-acetate-dependent increase in AP1 factor expression and binding to the hINV promoter and the increase in hINV promoter activity. Apigenin also inhibits the increase in promoter activity observed following overexpression of PKC, constitutively active Ras, or MEKK1. The suppression of PKC activity is associated with reduced phosphorylation of PKC-Y311. The physiological importance of this phosphorylation event was confirmed by showing that the PKC phosphorylation-defective mutant, PKC-Y311F, is less able to increase hINV promoter activity. Activation of hINV promoter activity by the green tea polyphenol, (-)-epigellocathecin-3-gallate, is also inhibited by apigenin, suggesting that the two chemopreventive agents can produce opposing actions in keratinocytes. Additional studies show that the apigenin-dependent suppression of differentiation is associated with reduced cell proliferation but that there is no evidence of apoptosis.

Received for publication, June 5, 2006 , and in revised form, September 7, 2006.

^* This work utilized the facilities of the Skin Diseases Research Center of Northeast Ohio (National Institutes of Health (NIH) Grant AR39750) and was supported by an NIH grant (to R. L. E.). 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.

¹ To whom correspondence should be addressed: Dept. of Physiology/Biophysics, Case Western Reserve University School of Medicine, 2109 Adelbert Rd., Cleveland, OH 44106-4970. Tel.: 216-368-5530; Fax: 216-368-5586; E-mail: rle2{at}po.cwru.edu.

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