DeltaNp63 transcriptionally regulates ATM to control p53 Serine-15 phosphorylation

DeltaNp63 alpha 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 DeltaNp63 alpha-positive cells in the basal layer of human epithelium.

Results: We now report that phosphorylation of the p53 tumour suppressor is positively regulated by DeltaNp63 alpha in immortalised human keratinocytes.

DeltaNp63 alpha depletion by RNAi reduces steady-state ATM mRNA and protein levels, and attenuates p53 Serine-15 phosphorylation. Conversely, ectopic expression of DeltaNp63 alpha in p63-null tumour cells stimulates ATM transcription and p53 Serine-15 phosphorylation.

We show that ATM is a direct DeltaNp63 alpha transcriptional target and that the DeltaNp63 alpha response element localizes to the ATM promoter CCAAT sequence. Structure-function analysis revealed that the DeltaNp63 alpha-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 DeltaNp63 alpha-ATM-p53 damage-response pathway may therefore function in epithelial development, carcinogenesis and the ageing processes.

Author: Ashley CraigJitka HolcakovaLee FinlanMarta NekulovaRoman HrstkaNuri GuevenJames DiRenzoGraeme SmithTed HuppBorivoj Vojtesek
Credits/Source: Molecular Cancer 2010, 9:195

Published on: 2010-07-21

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