Elwakeel Ahmed
Centre for Sport, Exercise, and Life Sciences (CSELS), Coventry University, Coventry, United Kingdom.
Front Cell Dev Biol. 2022 Apr 14;10:879632. doi: 10.3389/fcell.2022.879632. eCollection 2022.
p53 is a transcription factor that activates the expression of a set of genes that serve as a critical barrier to oncogenesis. Inactivation of p53 is the most common characteristic in sporadic human cancers. Mortalin is a differentially sub-cellularly localized member of the heat shock protein 70 family of chaperones that has essential mitochondrial and extra-mitochondrial functions. Elevated mortalin levels in multiple cancerous tissues and tumor-derived cell lines emphasized its key role in oncogenesis. One of mortalin's major oncogenic roles is the inactivation of p53. Mortalin binds to p53 sequestering it in the cytoplasm. Hence, p53 cannot freely shuttle to the nucleus to perform its tumor suppressor functions as a transcription factor. This protein-protein interaction was reported to be cancer-specific, hence, a selective druggable target for a rationalistic cancer therapeutic strategy. In this review article, the chronological identification of mortalin-p53 interactions is summarized, the challenges and general strategies for targeting protein-protein interactions are briefly discussed, and information about compounds that have been reported to abrogate mortalin-p53 interaction is provided. Finally, the reasons why the disruption of this druggable interaction has not yet been applied clinically are discussed.
p53是一种转录因子，可激活一组基因的表达，这些基因构成了肿瘤发生的关键屏障。p53失活是散发性人类癌症中最常见的特征。Mortalin是热休克蛋白70伴侣家族中一种亚细胞定位不同的成员，具有重要的线粒体和线粒体外功能。多种癌组织和肿瘤衍生细胞系中mortalin水平升高，凸显了其在肿瘤发生中的关键作用。Mortalin的主要致癌作用之一是使p53失活。Mortalin与p53结合，将其隔离在细胞质中。因此，p53无法自由穿梭到细胞核中，无法作为转录因子发挥其肿瘤抑制功能。据报道，这种蛋白质-蛋白质相互作用具有癌症特异性，因此，是合理癌症治疗策略中一个可选择性靶向的药物靶点。在这篇综述文章中，总结了mortalin与p53相互作用的时间顺序鉴定，简要讨论了靶向蛋白质-蛋白质相互作用的挑战和一般策略，并提供了有关已报道可消除mortalin-p53相互作用的化合物的信息。最后，讨论了这种可靶向相互作用尚未应用于临床的原因。
