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Published 30 January 2006. doi:10.1083/jcb.200510002
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 172, Number 3, 409-421
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Article

AP-2{alpha}: a regulator of EGF receptor signaling and proliferation in skin epidermis



Xuan Wang1,2, Diana Bolotin1,2, David H. Chu1,2, Lisa Polak1,2, Trevor Williams3,4, and Elaine Fuchs1,2

1 The Howard Hughes Medical Institute and 2 Laboratory of Mammalian Cell Biology and Development, Rockefeller University, New York, NY 10021
3 Department of Craniofacial Biology and 4 Department of Cell and Developmental Biology, University of Colorado Health Sciences Center, Denver, CO 80262

Correspondence to Elaine Fuchs: fuchs{at}rockefeller.edu

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-2{alpha} is essential for governing the balance between growth and differentiation in epidermis. In vivo, epidermis lacking AP-2{alpha} 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-2{alpha} repression, and, in the absence of AP-2{alpha}, this is manifested primarily in excessive EGF-dependent phosphoinositol-3 kinase/Akt activity. Together, our findings unveil a hitherto unrecognized repressive role for AP-2{alpha} 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-2{alpha} levels are often associated with terminal differentiation and why tumor cells often display reduced AP-2{alpha} and elevated EGFR proteins.

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.


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