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DeltaNp63 transcriptionally regulates ATM to control p53 Serine-15 phosphorylation

Citation

Craig, AL and Holcakova, J and Finlan, LE and Nekulova, M and Hrstka, R and Guven, N and Smith, G and DiRenzo, J and Hupp, TR and Vojtesek, B, DeltaNp63 transcriptionally regulates ATM to control p53 Serine-15 phosphorylation, Molecular Cancer, 9, (195) pp. 1-13. ISSN 1476-4598 (2010) [Refereed Article]


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Licenced under Creative Commons Attribution 2.0 Generic (CC BY 2.0) http://creativecommons.org/licenses/by/2.0/

DOI: doi:10.1186/1476-4598-9-195

Abstract

Abstract Background: Np63 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 Np63-positive cells in the basal layer of human epithelium. Results: We now report that phosphorylation of the p53 tumour suppressor is positively regulated by Np63 in immortalised human keratinocytes. Np63 depletion by RNAi reduces steady-state ATM mRNA and protein levels, and attenuates p53 Serine-15 phosphorylation. Conversely, ectopic expression of Np63 in p63-null tumour cells stimulates ATM transcription and p53 Serine-15 phosphorylation. We show that ATM is a direct Np63 transcriptional target and that the Np63 response element localizes to the ATM promoter CCAAT sequence. Structure-function analysis revealed that the Np63-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 Np63-ATM-p53 damage-response pathway may therefore function in epithelial development, carcinogenesis and the ageing processes.

Item Details

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
Author:Guven, N (Dr Nuri Guven)
ID Code:79272
Year Published:2010
Web of Science® Times Cited:23
Deposited By:Pharmacy
Deposited On:2012-08-29
Last Modified:2012-11-05
Downloads:465 View Download Statistics

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