Document Type

Article

Publication Date

7-21-2010

Publication Title

Molecular Cancer

Department

Geisel School of Medicine

Abstract

Background: ΔNp63α is an epithelial progenitor cell marker that maintains epidermal stem cell self-renewal capacity. Previous studies revealed that UV-dam age induced p53 phosphorylation is confined to ΔNp63α-positive cells in the basal layer of human epithelium. Results: We now report that phosphorylatio n of the p53 tumour suppressor is po sitively regulated by ΔNp63α in immortalised human keratinocytes. ΔNp63α depletion by RNAi reduces steady-state ATM mRNA and protein levels, and attenuates p53 Serine-15 phosphorylation. Conversely, ectopic expression of ΔNp63α in p63-null tumour cells stimulates ATM transcription and p53 Seri ne-15 phosphorylation. We show that AT M is a direct ΔNp63α transcriptional target and that the ΔNp63α response element localizes to the ATM promoter CCAAT sequence. Structure-function analysis revealed that the ΔNp63-specif ic 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 ΔNp63α-ATM-p53 damage-response pathway may therefore function in epithelial development, carcinogenesis and the ageing processes.

DOI

10.1186/1476-4598-9-195

Original Citation

Craig AL, Holcakova J, Finlan LE, Nekulova M, Hrstka R, Gueven N, DiRenzo J, Smith G, Hupp TR, Vojtesek B. DeltaNp63 transcriptionally regulates ATM to control p53 Serine-15 phosphorylation. Mol Cancer. 2010 Jul 21;9:195. doi: 10.1186/1476-4598-9-195. PMID: 20663147; PMCID: PMC3098010.

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