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J. Biol. Chem., Vol. 278, Issue 31, 28516-28522, August 1, 2003

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E2F Modulates Keratinocyte Squamous Differentiation

IMPLICATIONS FOR E2F INHIBITION IN SQUAMOUS CELL CARCINOMA^*

Chung Fai Wong  , Liam M. Barnes , Alison L. Dahler , Louise Smith , Magdalena M. Serewko-Auret  ¶, Claudia Popa  ||, Ibtissam Abdul-Jabbar  and Nicholas A. Saunders  ** 

From the Epithelial Pathobiology Group, Cancer Biology Programme, Centre for Immunology and Cancer Research, University of Queensland, Princess Alexandra Hospital, Woolloongabba, Australia 4102 and the ^**Department of Physiology and Pharmacology, University of Queensland, St. Lucia, Queensland, Australia, 4067

E2F regulation is essential for normal cell cycle progression. Therefore, it is not surprising that squamous cell carcinoma cell lines (SCC) overexpress E2F1 and exhibit deregulated E2F activity when compared with normal keratinocytes. Indeed, deliberate E2F1 deregulation has been shown to induce hyperplasia and skin tumor formation. In this study, we report on a dual role for E2F as a mediator of keratinocyte proliferation and modulator of squamous differentiation. Overexpression of E2F isoforms in confluent primary keratinocyte cultures resulted in suppression of differentiation-associated markers. Moreover, we found that the DNA binding domain and the trans-activation domain of E2F1 are important in mediating suppression of differentiation. Use of a dominant/negative form of E2F1 (E2F d/n) found that E2F inhibition alone is sufficient to suppress the activity of proliferation-associated markers but is not capable of inducing differentiation markers. However, if the E2F d/n is expressed in differentiated keratinocytes, differentiation marker activity is further induced, suggesting that E2F may act as a modulator of squamous differentiation. We therefore examined the effects of E2F d/n in a differentiation-insensitive SCC cell line. We found that treatment with the differentiating agent, 12-O-tetradecanoyl-phorbol-13-acetate (TPA), or expression of E2F d/n alone had no effect on differentiation markers. However, a combination of E2F d/n + TPA induced the expression of differentiation markers. Combined, these data indicate that E2F may play a key role in keratinocyte differentiation. These data also illustrate the unique potential of anti-E2F therapies in arresting proliferation and inducing differentiation of SCCs.

Received for publication, February 5, 2003 , and in revised form, May 15, 2003.

^* This work was supported by grants awarded from The Garnett Passe and Rodney Williams Memorial Foundation, The Australian National Health and Medical Research Council, and the Association for International Cancer Research. 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.

Sponsored by an Australian Postgraduate Award.

^¶ Funded by a Garnett Passe and Rodney Williams Memorial Foundation Postgraduate Scholarship.

^|| Supported by a University of Queensland Postdoctoral Fellowship.

Sponsored by a Senior Research Fellowship awarded by the Lions Medical Research Foundation. To whom correspondence should be addressed: Centre for Immunology and Cancer Research, University of Queensland, Princess Alexandra Hospital, 4th Floor Bldg. 1 R Wing, Ipswich Rd., Woolloongabba, Queensland, Australia 4102. Tel.: 07-3240-5936; Fax: 07-3240-5946; E-mail: nsaunders{at}cicr.uq.edu.au.

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