Open AccessAn Autoregulatory Loop Directs the Tissue-Specific Expression of p63 through a Long-Range Evolutionarily Conserved Enhancer
Author(s) -
Dario Antonini,
Barbara Rossi,
Rong Han,
Annunziata Minichiello,
Tina Di Palma,
Marcella Corrado,
Sandro Banfi,
Mariastella Zannini,
Janice L. Brissette,
Caterina Missero
Publication year - 2006
Publication title -
molecular and cellular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.14
H-Index - 327
eISSN - 1067-8824
pISSN - 0270-7306
DOI - 10.1128/mcb.26.8.3308-3318.2006
Subject(s) - biology , enhancer , gene isoform , transcription factor , microbiology and biotechnology , regulation of gene expression , gene expression , regulatory sequence , gene , genetics
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 controllingp63 spatial expression during development have not yet been defined. Using a genomic approach, we identified an evolutionarily conservedcis -regulatory element, located 160 kb downstream of the firstp63 exon, which functions as a keratinocyte-specific enhancer and is sufficient to recapitulate expression of the endogenous gene during mouse embryogenesis. Dissection of thep63 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 endogenousp63 expression in cells that do not normally express this gene, whereas dominant negative isoforms suppressp63 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 ofp63 expression during embryonic development and in adult cells.