AP-2alpha: a regulator of EGF receptor signaling and proliferation in skin epidermis.
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-2alpha is essential for governing the balance between growth and differentiation in epidermis. In vivo, epidermis lacking AP-2alpha 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-2alpha repression, and, in the absence of AP-2alpha, this is manifested primarily in excessive EGF-dependent phosphoinositol-3 kinase/Akt activity. Together, our findings unveil a hitherto unrecognized repressive role for AP-2alpha 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-2alpha levels are often associated with terminal differentiation and why tumor cells often display reduced AP-2alpha and elevated EGFR proteins.
Wang
Xuan
X
The Howard Hughes Medical Institute, Rockefeller University, New York, NY 10021, USA.
Bolotin
Diana
D
Chu
David H
DH
Polak
Lisa
L
Williams
Trevor
T
Fuchs
Elaine
E
D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000494:pharmacology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D002867:Chromones / Q000494:pharmacology; D004247:DNA / Q000235:genetics / Q000378:metabolism; D020405:Dermis / Q000378:metabolism; D004622:Embryo, Mammalian / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000078404:Epidermal Cells; D004815:Epidermal Growth Factor / Q000494:pharmacology; D004817:Epidermis / Q000502:physiology; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015870:Gene Expression / Q000235:genetics; D005786:Gene Expression Regulation; D006201:Hair Diseases / Q000235:genetics / Q000473:pathology; D019426:Integrases / Q000235:genetics; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D007633:Keratins / Q000378:metabolism; D019394:Ki-67 Antigen / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009025:Morpholines / Q000494:pharmacology; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D011799:Quinazolines; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D012867:Skin / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012868:Skin Abnormalities / Q000235:genetics / Q000473:pathology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D050656:Transcription Factor AP-2 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016211:Transforming Growth Factor alpha / Q000235:genetics; D020032:Tyrphostins / Q000494:pharmacology
D002867:Chromones; D004791:Enzyme Inhibitors; D019394:Ki-67 Antigen; D009025:Morpholines; D011799:Quinazolines; D050656:Transcription Factor AP-2; D016211:Transforming Growth Factor alpha; D020032:Tyrphostins; C101044:RTKI cpd; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D004815:Epidermal Growth Factor; D007633:Keratins; D004247:DNA; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; C045073:Cre recombinase; D019426:Integrases; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium