![]() However, as shown in Figure 1, oncogenic signaling activation induces the p14 ARF tumor suppressor to bind to MDM2 preventing its interaction with p53 ( Weber et al., 1999 Pomerantz et al., 1998) leading to p53 post-translational modification, stabilization, and translocation to the nucleus to transactivate a set of genes responsible for the quite well-understood tumor suppression programs (apoptosis, cell cycle arrest and cell senescence). Under normal physiological conditions, p53 protein is kept at low levels by means of murine double minute 2 (MDM2), an E3 ubiquitin ligase that directs p53 to degradation by the cellular proteasome machinery. P53 is a sequence-specific DNA binding protein that regulates the transcription of more than 350 confirmed target genes reported from individual gene analyses ( Fischer, 2017). Finally, the reasons why the disruption of this druggable interaction has not yet been applied clinically are discussed. 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. This protein-protein interaction was reported to be cancer-specific, hence, a selective druggable target for a rationalistic cancer therapeutic strategy. Hence, p53 cannot freely shuttle to the nucleus to perform its tumor suppressor functions as a transcription factor. Mortalin binds to p53 sequestering it in the cytoplasm. One of mortalin’s major oncogenic roles is the inactivation of p53. ![]() Elevated mortalin levels in multiple cancerous tissues and tumor-derived cell lines emphasized its key role in oncogenesis. 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. Inactivation of p53 is the most common characteristic in sporadic human cancers. P53 is a transcription factor that activates the expression of a set of genes that serve as a critical barrier to oncogenesis. Centre for Sport, Exercise, and Life Sciences (CSELS), Coventry University, Coventry, United Kingdom.
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