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Molecular and Cellular Biology, April 2006, p. 3308-3318, Vol. 26, No. 8
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.8.3308-3318.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

An Autoregulatory Loop Directs the Tissue-Specific Expression of p63 through a Long-Range Evolutionarily Conserved Enhancer

Dario Antonini,¹ Barbara Rossi,¹ Rong Han,² Annunziata Minichiello,¹ Tina Di Palma,³ Marcella Corrado,^1, Sandro Banfi,¹ Mariastella Zannini,³ Janice L. Brissette,² and Caterina Missero^1*

Telethon Institute of Genetics and Medicine, 80131 Napoli, Italy,¹ Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129,² Istituto di Endocrinologia ed Oncologia Sperimentale-CNR, Dipartimento di Biologia e Patologia Cellulare e Molecolare, University Federico II, 80131 Napoli, Italy³

Received 30 September 2005/ Returned for modification 4 November 2005/ Accepted 28 January 2006

p63, a p53 family member, is essential for the development of various stratified epithelia and is one of the earliest markers of many ectodermal structures, including the epidermis, oral mucosa, apical ectodermal ridge, and mammary gland. Genetic regulatory mechanisms controlling p63 spatial expression during development have not yet been defined. Using a genomic approach, we identified an evolutionarily conserved cis-regulatory element, located 160 kb downstream of the first p63 exon, which functions as a keratinocyte-specific enhancer and is sufficient to recapitulate expression of the endogenous gene during mouse embryogenesis. Dissection of the p63 enhancer activity revealed a positive autoregulatory loop in which the p63 proteins directly bind to and are essential regulators of the enhancer. Accordingly, transactivating p63 isoforms induce endogenous p63 expression in cells that do not normally express this gene, whereas dominant negative isoforms suppress p63 expression in keratinocytes. In addition the transcription factor AP-2 also binds to the enhancer and cooperates with p63 to induce its activity. These results demonstrate that a long-range autoregulatory loop is involved in the regulation of p63 expression during embryonic development and in adult cells.

Supplemental material for this article may be found at http://mcb.asm.org/.

Present address: Dipartimento Materno Infantile e Tecnologie Biomediche, University of Brescia, 25123 Brescia, Italy.

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