ΔNp63 transcriptionally regulates ATM to control p53 Serine-15 phosphorylation

被引:31
作者
Craig, Ashley L. [2 ]
Holcakova, Jitka [1 ]
Finlan, Lee E. [2 ]
Nekulova, Marta [1 ]
Hrstka, Roman [1 ]
Gueven, Nuri [3 ]
DiRenzo, James [4 ]
Smith, Graeme [5 ]
Hupp, Ted R. [2 ]
Vojtesek, Borivoj [1 ]
机构
[1] Masaryk Mem Canc Inst, Brno 65653, Czech Republic
[2] Univ Edinburgh, Western Gen Hosp, Cell Signalling Unit, Canc Res Ctr, Edinburgh EH4 2XR, Midlothian, Scotland
[3] Queensland Inst Med Res, Brisbane, Qld 4029, Australia
[4] Dartmouth Med Sch, Dept Pharmacol & Toxicol, Hanover, NH 03755 USA
[5] KuDOS Pharmaceut Ltd, Cambridge CB4 0WG, England
来源
MOLECULAR CANCER | 2010年 / 9卷
关键词
DNA-BINDING DOMAIN; HAY-WELLS-SYNDROME; STEM-CELLS; DEPENDENT PHOSPHORYLATION; DIFFERENTIAL REGULATION; ATAXIA-TELANGIECTASIA; IONIZING-RADIATION; TUMOR-SUPPRESSOR; P63; ISOFORMS; TARGET GENES;
D O I
10.1186/1476-4598-9-195
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Background: Delta Np63 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 Delta Np63 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 Delta Np63 alpha in immortalised human keratinocytes. Delta Np63 alpha depletion by RNAi reduces steady-state ATM mRNA and protein levels, and attenuates p53 Serine-15 phosphorylation. Conversely, ectopic expression of Delta Np63 alpha in p63-null tumour cells stimulates ATM transcription and p53 Serine-15 phosphorylation. We show that ATM is a direct Delta Np63 alpha transcriptional target and that the Delta Np63 alpha response element localizes to the ATM promoter CCAAT sequence. Structure-function analysis revealed that the Delta 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 Delta Np63 alpha-ATM-p53 damage-response pathway may therefore function in epithelial development, carcinogenesis and the ageing processes.
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页数:13
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