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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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