Hansen T M, Rossi M, Roperch J P, Ansell K, Simpson K, Taylor D, Mathon N, Knight R A, Melino G
Medical Research Council, Toxicology Unit, Hodgkin Building, P.O. Box 138, Leicester University, Lancaster Road, Leicester LE1 9HN, UK.
Biochem Biophys Res Commun. 2007 Sep 14;361(1):33-6. doi: 10.1016/j.bbrc.2007.06.104. Epub 2007 Jun 25.
Itch is a member of the HECT family of ubiquitin E3 ligases, and regulates the stability of several proteins involved in response to genotoxic stress. We have previously shown that p73 and p63, two members of the p53 family of tumour suppressors, are targets for Itch-mediated ubiquitylation and degradation. Here, we show that depletion of Itch by RNA interference augments apoptosis upon treatment with chemotherapeutic drugs. We also show that cells with no functional p53 are more sensitive to Itch depletion, highlighting the importance that changes in levels of Itch may play in majority of cancers, where p53 is absent or mutated. Furthermore, reintroduction of Itch in fibroblasts obtained from Itch deficient mice results in reduced cell death upon DNA damage. Overall our findings suggest that inhibition of Itch potentiates the effect of chemotherapeutic drugs revealing the pharmacological potentials of targeting Itch for cancer therapy.
ITCH是泛素E3连接酶HECT家族的成员，可调节几种参与对基因毒性应激反应的蛋白质的稳定性。我们之前已经表明，肿瘤抑制因子p53家族的两个成员p73和p63是ITCH介导的泛素化和降解的靶点。在此，我们表明，通过RNA干扰使ITCH缺失会增强化疗药物处理后的细胞凋亡。我们还表明，没有功能性p53的细胞对ITCH缺失更敏感，这突出了ITCH水平变化在大多数p53缺失或突变的癌症中可能发挥的重要性。此外，将ITCH重新引入从ITCH缺陷小鼠获得的成纤维细胞中会导致DNA损伤后细胞死亡减少。总体而言，我们的研究结果表明，抑制ITCH可增强化疗药物的效果，揭示了将ITCH作为癌症治疗靶点的药理学潜力。
