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Abstract Background: ÄNp63á is an epithelial progenitor cell marker that maintains epidermal stem cell self-renewal capacity.Previous studies revealed that UV-damage induced p53 phosphorylation is confined to ÄNp63á-positive cells in the basal layer of human epithelium. Results: We now report that phosphorylation of the p53 tumour suppressor is positively regulated by ÄNp63á in immortalised human keratinocytes. ÄNp63á depletion by RNAi reduces steady-state ATM mRNA and protein levels, and attenuates p53 Serine-15 phosphorylation. Conversely, ectopic expression of ÄNp63á in p63-null tumour cells stimulates ATM transcription and p53 Serine-15 phosphorylation. We show that ATM is a direct ÄNp63á transcriptional target and that the ÄNp63á response element localizes to the ATM promoter CCAAT sequence. Structure-function analysis revealed that the ÄNp63-specific TA2 transactivation domain mediates ATM transcription in coordination with the DNA binding and SAM domains. Conclusions: Germline p63 point mutations are associated with a range of ectodermal developmental disorders, and targeted p63 deletion in the skin causes premature ageing. The ÄNp63á-ATM-p53 damage-response pathway may therefore function in epithelial development, carcinogenesis and the ageing processes.

Item Type:	Refereed Article
Keywords:	ATM, p53, p63 phosphorylation
Research Division:	Biological Sciences
Research Group:	Biochemistry and Cell Biology
Research Field:	Signal Transduction
Objective Division:	Expanding Knowledge
Objective Group:	Expanding Knowledge
Objective Field:	Expanding Knowledge in the Biological Sciences
UTAS Author:	Guven, N (Dr Nuri Guven)
ID Code:	79272
Year Published:	2010
Web of Science® Times Cited:	24
Deposited By:	Pharmacy
Deposited On:	2012-08-29
Last Modified:	2012-11-05
Downloads:	482 View Download Statistics