AP-2 transcription factors have been implicated in epidermal biology, but their functional significance has remained elusive. Using conditional knockout technology, we show that AP-2α is essential for governing the balance between growth and differentiation in epidermis. In vivo, epidermis lacking AP-2α exhibits elevated expression of the epidermal growth factor receptor (EGFR) in the differentiating layers, resulting in hyperproliferation when the receptors are activated. Chromatin immunoprecipitation and promoter activity assays identify EGFR as a direct target gene for AP-2α repression, and, in the absence of AP-2α, this is manifested primarily in excessive EGF-dependent phosphoinositol-3 kinase/Akt activity. Together, our findings unveil a hitherto unrecognized repressive role for AP-2α in governing EGFR gene transcription as cells exit the basal layer and withdraw from the cell cycle. These results provide insights into why elevated AP-2α levels are often associated with terminal differentiation and why tumor cells often display reduced AP-2α and elevated EGFR proteins.
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30 January 2006
Article|
January 30 2006
AP-2α: a regulator of EGF receptor signaling and proliferation in skin epidermis
Xuan Wang,
Xuan Wang
1The Howard Hughes Medical Institute and
2Laboratory of Mammalian Cell Biology and Development, Rockefeller University, New York, NY 10021
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Diana Bolotin,
Diana Bolotin
1The Howard Hughes Medical Institute and
2Laboratory of Mammalian Cell Biology and Development, Rockefeller University, New York, NY 10021
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David H. Chu,
David H. Chu
1The Howard Hughes Medical Institute and
2Laboratory of Mammalian Cell Biology and Development, Rockefeller University, New York, NY 10021
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Lisa Polak,
Lisa Polak
1The Howard Hughes Medical Institute and
2Laboratory of Mammalian Cell Biology and Development, Rockefeller University, New York, NY 10021
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Trevor Williams,
Trevor Williams
3Department of Craniofacial Biology and
4Department of Cell and Developmental Biology, University of Colorado Health Sciences Center, Denver, CO 80262
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Elaine Fuchs
Elaine Fuchs
1The Howard Hughes Medical Institute and
2Laboratory of Mammalian Cell Biology and Development, Rockefeller University, New York, NY 10021
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Xuan Wang
1The Howard Hughes Medical Institute and
2Laboratory of Mammalian Cell Biology and Development, Rockefeller University, New York, NY 10021
Diana Bolotin
1The Howard Hughes Medical Institute and
2Laboratory of Mammalian Cell Biology and Development, Rockefeller University, New York, NY 10021
David H. Chu
1The Howard Hughes Medical Institute and
2Laboratory of Mammalian Cell Biology and Development, Rockefeller University, New York, NY 10021
Lisa Polak
1The Howard Hughes Medical Institute and
2Laboratory of Mammalian Cell Biology and Development, Rockefeller University, New York, NY 10021
Trevor Williams
3Department of Craniofacial Biology and
4Department of Cell and Developmental Biology, University of Colorado Health Sciences Center, Denver, CO 80262
Elaine Fuchs
1The Howard Hughes Medical Institute and
2Laboratory of Mammalian Cell Biology and Development, Rockefeller University, New York, NY 10021
Correspondence to Elaine Fuchs: [email protected]
X. Wang and D. Bolotin contributed equally to this paper.
D. Bolotin's present address is Department of Molecular Genetics and Cell Biology, The University of Chicago, Chicago, IL 60637.
Abbreviations used in this paper: ChIP, chromatin immunoprecipitation; cKO, conditional KO; EGFR, EGF receptor; IGF, insulin growth factor; KO, knockout; PI3K, phosphoinositol-3 kinase; TPA, 12-O-tetradecanoylphorbol-13-acetate; WT, wild type.
Received:
October 03 2005
Accepted:
December 22 2005
Online ISSN: 1540-8140
Print ISSN: 0021-9525
The Rockefeller University Press
2006
J Cell Biol (2006) 172 (3): 409–421.
Article history
Received:
October 03 2005
Accepted:
December 22 2005
Citation
Xuan Wang, Diana Bolotin, David H. Chu, Lisa Polak, Trevor Williams, Elaine Fuchs; AP-2α: a regulator of EGF receptor signaling and proliferation in skin epidermis . J Cell Biol 30 January 2006; 172 (3): 409–421. doi: https://doi.org/10.1083/jcb.200510002
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