Physical and functional interaction between p53 and the Werner's syndrome protein
Physical and functional interaction between p53 and the Werner's syndrome protein
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DOI：
10.1074/jbc.274.41.29463
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发表时间：
1999-10-08
影响因子：
4.8
通讯作者：
Oren, M
中科院分区：
文献类型：
--
作者：
Blander, G;Kipnis, J;Oren, M
沃纳氏综合症是一种导致过早衰老的人类常染色体隐性遗传疾病。最近，导致这种疾病的突变被定位于编码具有 DNA 解旋酶和核酸外切酶活性的蛋白质的基因 (WRN)。携带 WRN 基因突变的患者患癌症的几率较高，并伴随着基因组不稳定性的增加。后者的特征也是 p53 功能丧失的特征，p53 是一种肿瘤抑制因子，在人类癌症中经常失活。此外，p53 活性的变化与细胞复制衰老的发生有关。我们在这里报道WRN蛋白可以与p53形成特定的物理相互作用。这种相互作用涉及 WRN 的羧基末端部分和 p53 的末端羧基末端，该区域在调节 p53 的功能状态中发挥重要作用。在未转染的细胞中可以发现一小部分 WRN 与内源性 p53 形成复合物。 WRN 的过度表达会增强 p53 依赖性转录活性并诱导 p21(Waf1) 蛋白表达。这些发现支持 WRN 和 p53 之间存在串扰，这对于维持基因组完整性和防止可能导致过早衰老和癌症的畸变积累可能很重要。
Werner's syndrome is a human autosomal recessive disorder leading to premature aging. The mutations responsible for this disorder have recently been localized to a gene (WRN) encoding a protein that possesses DNA helicase and exonuclease activities. Patients carrying WRN gene mutations exhibit an elevated rate of cancer, accompanied by increased genomic instability. The latter features are also characteristic of the loss of function of p53, a tumor suppressor that is very frequently inactivated in human cancer. Moreover, changes in the activity of p53 have been implicated in the onset of cellular replicative senescence. We report here that the WRN protein can form a specific physical interaction with p53. This interaction involves the carboxyl-terminal part of WRN and the extreme carboxyl terminus of p53, a region that plays an important role in regulating the functional state of p53. A small fraction of WRN can be found in complex with endogenous p53 in nontransfected cells. Overexpression of WRN leads to augmented p53-dependent transcriptional activity and induction of p21(Waf1) protein expression. These findings support the existence of a cross-talk between WRN and p53, which may be important for maintaining genomic integrity and for preventing the accumulation of aberrations that can give rise to premature senescence and cancer.