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Molecular Cancer
Published in: Molecular Cancer 1/2010

Open Access 01-12-2010 | Research

ΔNp63 transcriptionally regulates ATM to control p53 Serine-15 phosphorylation

Authors: Ashley L Craig, Jitka Holcakova, Lee E Finlan, Marta Nekulova, Roman Hrstka, Nuri Gueven, James DiRenzo, Graeme Smith, Ted R Hupp, Borivoj Vojtesek

Published in: Molecular Cancer | Issue 1/2010

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Abstract

Background

ΔNp63α 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 ΔNp63α-positive cells in the basal layer of human epithelium.

Results

We now report that phosphorylation of the p53 tumour suppressor is positively 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 Serine-15 phosphorylation. We show that ATM 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-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 ΔNp63α-ATM-p53 damage-response pathway may therefore function in epithelial development, carcinogenesis and the ageing processes.
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Metadata
Title
ΔNp63 transcriptionally regulates ATM to control p53 Serine-15 phosphorylation
Authors
Ashley L Craig
Jitka Holcakova
Lee E Finlan
Marta Nekulova
Roman Hrstka
Nuri Gueven
James DiRenzo
Graeme Smith
Ted R Hupp
Borivoj Vojtesek
Publication date
01-12-2010
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2010
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/1476-4598-9-195

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