Mosser Dick D, Morimoto Richard I
Department of Molecular Biology and Genetics, University of Guelph, Guelph, Ontario, Canada N1G 2W1.
Oncogene. 2004 Apr 12;23(16):2907-18. doi: 10.1038/sj.onc.1207529.
Protein-damaging stresses induce the expression of 'heat-shock proteins', which have essential roles in protecting cells from the potentially lethal effects of stress and proteotoxicity. These stress-protective heat-shock proteins are often overexpressed in cells of various cancers and have been suggested to be contributing factors in tumorigenesis. An underlying basis of oncogenesis is the acquisition and accumulation of mutations that provide the transformed cell with the combined characteristics of deregulated cell proliferation and suppressed cell death. Heat-shock proteins with dual roles as regulators of protein conformation and stress sensors may therefore have intriguing and central roles in both cell proliferation and apoptosis. It has been established that heat-shock proteins exhibit specificity to particular classes of polypeptide substrates and client proteins in vivo, and that chaperones can stabilize mutations that affect the folded conformation. Likewise, overexpression of chaperones has also been shown to protect cells against apoptotic cell death. The involvement of chaperones, therefore, in such diverse roles might suggest novel anticancer therapeutic approaches targeting heat-shock protein function for a broad spectrum of tumor types.
蛋白质损伤应激会诱导“热休克蛋白”的表达，热休克蛋白在保护细胞免受应激和蛋白毒性的潜在致命影响方面发挥着重要作用。这些具有应激保护作用的热休克蛋白在各种癌症细胞中常常过度表达，并且被认为是肿瘤发生的促成因素。肿瘤发生的一个潜在基础是突变的获得和积累，这些突变赋予转化细胞不受调控的细胞增殖和受抑制的细胞死亡的综合特征。因此，兼具蛋白质构象调节因子和应激传感器双重作用的热休克蛋白可能在细胞增殖和凋亡中都具有引人关注的核心作用。已经确定，热休克蛋白在体内对特定类别的多肽底物和客户蛋白具有特异性，并且伴侣蛋白可以稳定影响折叠构象的突变。同样，伴侣蛋白的过度表达也已被证明能保护细胞免受凋亡性细胞死亡。因此，伴侣蛋白参与如此多样的作用可能暗示针对热休克蛋白功能的新型抗癌治疗方法可用于广泛的肿瘤类型。
