Kinase requirements in human cells: V. Synthetic lethal interactions between p53 and the protein kinases SGK2 and PAK3
Kinase requirements in human cells: V. Synthetic lethal interactions between p53 and the protein kinases SGK2 and PAK3
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DOI：
10.1073/pnas.1007462107
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发表时间：
2010-07-13
影响因子：
11.1
通讯作者：
Munger, Karl
中科院分区：
文献类型：
--
作者：
Baldwin, Amy;Grueneberg, Dorre A.;Munger, Karl
宫颈癌是通过一系列明确的阶段开始的，这些阶段依赖于人乳头瘤病毒（HPV）癌基因的表达。一组靶向许多肿瘤类型中的必需激酶的100个小发夹RNA用于研究宫颈肿瘤发展期间激酶需求的逐步出现。26激酶通常需要在三个细胞系来自坦率的癌，每个激酶的要求追溯到特定的阶段，在该要求出现。HPV诱导的永生化后需要6种激酶，而对SGK 2和PAK 3这两种激酶的需求与原代人上皮细胞中p53的失活有关。其他原代上皮细胞中p53肿瘤抑制因子的缺失也诱导了对SGK 2和PAK 3的依赖。因此，SGK 2和PAK 3在p53失活后提供重要的细胞功能，满足合成致死性的经典定义;单独的p53、SGK 2或PAK 3的损失对细胞活力几乎没有影响，而p53的损失与SGK 2或PAK 3的损失一起导致细胞死亡。虽然肿瘤抑制基因突变不是直接可药物化的，但在肿瘤抑制基因丧失后成为细胞活力必需的其他蛋白质或途径为肿瘤抑制基因特异性药物发现工作提供了理论靶点。因此，激酶SGK 2和PAK 3可能代表p53特异性药物开发的此类靶标。
Cervical carcinomas are initiated through a series of well-defined stages that rely on the expression of human papillomavirus (HPV) oncogenes. A panel of 100 small hairpin RNAs that target essential kinases in many tumor types was used to study the stepwise appearance of kinase requirements during cervical tumor development. Twenty-six kinases were commonly required in three cell lines derived from frank carcinomas, and each kinase requirement was traced to the specific stage in which the requirement emerged. Six kinases became required following HPV-induced immortalization, and the requirement for two kinases, SGK2 and PAK3, was mapped to the inactivation of p53 in primary human epithelial cells. Loss of the p53 tumor suppressor in other primary epithelial cells also induced dependence on SGK2 and PAK3. Hence, SGK2 and PAK3 provide important cellular functions following p53 inactivation, fulfilling the classical definition of synthetic lethality; loss of p53, SGK2, or PAK3 alone has little effect on cell viability, whereas loss of p53 together with either SGK2 or PAK3 loss leads to cell death. Whereas tumor suppressor gene mutations are not directly druggable, other proteins or pathways that become obligatory to cell viability following tumor suppressor loss provide theoretical targets for tumor suppressor-specific drug discovery efforts. The kinases SGK2 and PAK3 may thus represent such targets for p53-specific drug development.