Destabilization of CHK2 by a missense mutation associated with Li-Fraumeni Syndrome.
Destabilization of CHK2 by a missense mutation associated with Li-Fraumeni Syndrome.
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发表时间：
2001-11
期刊：
影响因子：
11.2
通讯作者：
Sean-Bong Lee;S. H. Kim;D. Bell;D. Wahrer;T. Schiripo;Melissa M. Jorczak;D. Sgroi;J. Garber
中科院分区：
文献类型：
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作者：
Sean-Bong Lee;S. H. Kim;D. Bell;D. Wahrer;T. Schiripo;Melissa M. Jorczak;D. Sgroi;J. Garber
Li Fraumeni综合征（LFS）是一种多癌表型，最常见的与TP53的生殖系突变相关。在一个没有遗传性TP 53突变的LFS亲属中，我们之前报道了CHK 2中的截短突变（1100 delC），编码一种使Ser上的p53磷酸化的激酶（20）。在这里，我们描述了CHK2错义突变（R145W）在另一个LFS家庭。这种突变使编码的蛋白质不稳定，使其半衰期从>120分钟缩短至30分钟。这种作用通过用蛋白体抑制剂处理细胞而消除，表明CHK2（R145W）通过这种降解途径被靶向。CHK2中的1100delC和R145W种系突变均与相应肿瘤标本中野生型等位基因的丢失相关，并且两种肿瘤均不携带体细胞TP53突变。我们的观察结果支持CHK2突变在罕见LFS病例中的功能意义，并表明此类突变可能取代TP53的失活。
Li Fraumeni Syndrome (LFS) is a multicancer phenotype, most commonly associated with germ-line mutations in TP53. In a kindred with LFS without an inherited TP53 mutation, we have previously reported a truncating mutation (1100delC) in CHK2, encoding a kinase that phosphorylates p53 on Ser(20). Here, we describe a CHK2 missense mutation (R145W) in another LFS family. This mutation destabilizes the encoded protein, reducing its half-life from >120 min to 30 min. This effect is abrogated by treatment of cells with a proteosome inhibitor, suggesting that CHK2(R145W) is targeted through this degradation pathway. Both 1100delC and R145W germ-line mutations in CHK2 are associated with loss of the wild-type allele in the corresponding tumor specimens, and neither tumor harbors a somatic TP53 mutation. Our observations support the functional significance of CHK2 mutations in rare cases of LFS and suggest that such mutations may substitute for inactivation of TP53.