Department of Urology, SUNY Upstate Medical University, Syracuse, NY 13210, USA.
Upstate Cancer Center, SUNY Upstate Medical University, Syracuse, NY 13210, USA.
Oncotarget. 2024 Oct 1;15:679-696. doi: 10.18632/oncotarget.28653.
The term 'tumor suppressor' describes a widely diverse set of genes that are generally involved in the suppression of metastasis, but lead to tumorigenesis upon loss-of-function mutations. Despite the protein products of tumor suppressors exhibiting drastically different structures and functions, many share a common regulatory mechanism-they are molecular chaperone 'clients'. Clients of molecular chaperones depend on an intracellular network of chaperones and co-chaperones to maintain stability. Mutations of tumor suppressors that disrupt proper chaperoning prevent the cell from maintaining sufficient protein levels for physiological function. This review discusses the role of the molecular chaperones Hsp70 and Hsp90 in maintaining the stability and functional integrity of tumor suppressors. The contribution of cochaperones prefoldin, HOP, Aha1, p23, FNIP1/2 and Tsc1 as well as the chaperonin TRiC to tumor suppressor stability is also discussed. Genes implicated in renal cell carcinoma development-, , and -will be used as examples to explore this concept, as well as how pathogenic mutations of tumor suppressors cause disease by disrupting protein chaperoning, maturation, and function.
“肿瘤抑制因子”一词描述了一组广泛多样的基因，这些基因通常参与抑制转移，但在功能丧失性突变时会导致肿瘤发生。尽管肿瘤抑制因子的蛋白质产物表现出截然不同的结构和功能，但许多都具有共同的调节机制——它们是分子伴侣“客户”。分子伴侣的客户依赖于细胞内的伴侣蛋白和共伴侣蛋白网络来维持稳定性。破坏适当伴侣蛋白作用的肿瘤抑制因子突变会阻止细胞维持足够的蛋白质水平以维持生理功能。本文讨论了分子伴侣 Hsp70 和 Hsp90 在维持肿瘤抑制因子稳定性和功能完整性方面的作用。还讨论了伴侣蛋白 prefoldingin、HOP、Aha1、p23、FNIP1/2 和 Tsc1 以及 chaperonin TRiC 对肿瘤抑制因子稳定性的贡献。本文还将使用与肾细胞癌发展相关的基因——、和——作为示例来探讨这一概念，以及肿瘤抑制因子的致病性突变如何通过破坏蛋白质伴侣蛋白作用、成熟和功能导致疾病。
