Abrogating the Interaction Between p53 and Mortalin (Grp75/HSPA9/mtHsp70) for Cancer Therapy: The Story so far

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    Abstract

    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 extramitochondrial 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.
    Original languageEnglish
    Article number879632
    Number of pages15
    JournalFrontiers in Cell and Developmental Biology
    Volume10
    DOIs
    Publication statusPublished - 14 Apr 2022

    Bibliographical note

    This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    Funder

    Open Access (OA) publishing costs were supported by Coventry University.

    Keywords

    • mortalin
    • p53
    • Drug Discovery
    • Inhibitors
    • mortalin-p53 interaction
    • Protein-protein interactions

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