Somatic mutations of the Parkinson's disease-associated gene PARK2 in glioblastoma and other human malignancies.
Somatic mutations of the Parkinson's disease-associated gene PARK2 in glioblastoma and other human malignancies.
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编码一种E3泛素连接酶的PARK2基因发生突变是早发性帕金森病最常见的病因。在寻找多位点肿瘤抑制因子的过程中，我们发现PARK2是癌症中6q25.2 - q27号染色体上一个频繁成为靶点的基因。在此我们描述了人类恶性肿瘤中PARK2基因的失活性体细胞突变以及频繁的基因内缺失情况。癌症中的PARK2突变发生在与导致家族性帕金森病的种系突变相同的结构域，有时甚至在相同的残基上。癌症特异性突变消除了PARK2蛋白的生长抑制作用。癌症中的PARK2突变降低了PARK2的E3连接酶活性，损害了其使细胞周期蛋白E泛素化的能力，从而导致有丝分裂不稳定。这些数据有力地表明PARK2是6q25.2 - q27上的一个肿瘤抑制因子。因此，PARK2这个在种系中发生突变时会导致神经元功能障碍的基因，当在非神经元体细胞中发生改变时，可能反而会促进肿瘤发生。
Mutation of the gene PARK2, which encodes an E3 ubiquitin ligase, is the most common cause of early-onset Parkinson's disease. In a search for multisite tumor suppressors, we identified PARK2 as a frequently targeted gene on chromosome 6q25.2–q27 in cancer. Here we describe inactivating somatic mutations and frequent intragenic deletions of PARK2 in human malignancies. The PARK2 mutations in cancer occur in the same domains, and sometimes at the same residues, as the germline mutations causing familial Parkinson's disease. Cancer-specific mutations abrogate the growth-suppressive effects of the PARK2 protein. PARK2 mutations in cancer decrease PARK2's E3 ligase activity, compromising its ability to ubiquitinate cyclin E and resulting in mitotic instability. These data strongly point to PARK2 as a tumor suppressor on 6q25.2–q27. Thus, PARK2, a gene that causes neuronal dysfunction when mutated in the germline, may instead contribute to oncogenesis when altered in non-neuronal somatic cells.