Differential protein expression, DNA binding and interaction with SV40 large tumour antigen implicate the p63-family of proteins in replicative senescence

被引:15
作者
Djelloul, S
Tarunina, M
Barnouin, K
Mackay, A
Jat, PS
机构
[1] Royal Free & Univ Coll Sch Med, Ludwig Inst Canc Res, London W1W 7BS, England
[2] UCL, Dept Biochem & Mol Biol, London WC1E 6BT, England
[3] Royal Free & Univ Coll Sch Med, Dept Surg, LICR UCL Breast Canc Lab, London W1P 7LD, England
关键词
p63; p53; replicative senescence; DNA binding; SV40; T-antigen;
D O I
10.1038/sj.onc.1205253
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
P53 activity plays a key role in mammalian cells when they undergo replicative senescence at their Hayflick limit. To determine whether p63 proteins, members of the family of p53-related genes, are also involved in this process, we examined their expression in serially passaged rat embryo fibroblasts. Upon senescence, two truncated DeltaNp63 proteins decreased in abundance whereas two TAp63 isoforms accumulated. 2-D get analysis showed that the DeltaNp63 proteins underwent post-translational modifications in both proliferating and senescent cells. Direct binding of DeltaNp63 proteins to a p53 consensus motif was greater in proliferating cells than senescent cells. In contrast p63alpha isoforms bound to DNA in a p53 dependent manner and this was higher in senescent cells than proliferating cells. An interaction of p63alpha proteins with SV40 large tumour antigen was also detected and ectopic expression of DeltaNp63alpha can extend the lifespan of rat embryo fibroblasts. Taken together the results indicate that p63 proteins may play a role in replicative senescence either by competition for p53 DNA binding sites or by direct interaction with p53 protein bound to DNA.
引用
收藏
页码:981 / 989
页数:9
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