Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 3308-3318 |
| Number of pages | 11 |
| Journal | Molecular and Cellular Biology |
| Volume | 26 |
| Issue number | 8 |
| DOIs | |
| Publication status | Published - Apr 2006 |
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ASJC Scopus subject areas
- Molecular Biology
- Genetics
- Cell Biology
Cite this
An autoregulatory loop directs the tissue-specific expression of p63 through a long-range evolutionarily conserved enhancer. / Antonini, Dario; Rossi, Barbara; Han, Rong; Minichiello, Annunziata; Di Palma, Tina; Corrado, Marcella; Banfi, Sandro; Zannini, Mariastella; Brissette, Janice L.; Missero, Caterina.
In: Molecular and Cellular Biology, Vol. 26, No. 8, 04.2006, p. 3308-3318.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - An autoregulatory loop directs the tissue-specific expression of p63 through a long-range evolutionarily conserved enhancer
AU - Antonini, Dario
AU - Rossi, Barbara
AU - Han, Rong
AU - Minichiello, Annunziata
AU - Di Palma, Tina
AU - Corrado, Marcella
AU - Banfi, Sandro
AU - Zannini, Mariastella
AU - Brissette, Janice L.
AU - Missero, Caterina
PY - 2006/4
Y1 - 2006/4
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=33645829469&partnerID=8YFLogxK
U2 - 10.1128/MCB.26.8.3308-3318.2006
DO - 10.1128/MCB.26.8.3308-3318.2006
M3 - Article
C2 - 16581802
AN - SCOPUS:33645829469
VL - 26
SP - 3308
EP - 3318
JO - Molecular and Cellular Biology
JF - Molecular and Cellular Biology
SN - 0270-7306
IS - 8
ER -