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p53-Hsp90 Axis in Human Cancer

  • Amr Ghaleb
  • Natalia MarchenkoEmail author
Chapter
Part of the Heat Shock Proteins book series (HESP, volume 19)

Abstract

The heat shock protein 90 (Hsp90) is a ubiquitous molecular chaperone that is abundantly expressed in cancer cells and plays a pivotal role in correct folding and functions of a variety of oncogenic clients. Hsp90 is up-regulated in response to cellular stresses that cancer cells encounter, such as heat, hypoxia and nutrient deprivation, conditions commonly associated with the tumor microenvironment. P53 is the tumor suppressor gene that is mutated in nearly 50% of all human cancers. When mutated p53 not only lose its tumor suppressive function but also gain novel oncogenic activities via gain-of-function mechanisms leading to increased genomic instability, chemoresistance, and metastasis, which promote tumor progression. In contrast to wild-type p53, mutant p53 is protected from degradation via interaction with Hsp90 leading to marked stabilization of mutant p53 protein in cancer cells. Recent in vivo studies unequivocally have proven that the stabilization of mutant p53 is crucial pre-requisite for its oncogenic functions. The pharmacological targeting the pathways involved in the stabilization of mutant p53, in particular, the Hsp90 chaperone complex, recently attracted a lot of attention as a promising therapeutic approach to treat mutant p53 harboring cancers.

Keywords

Cancer Gain-of-function Heat shock protein Hsp90 Loss of heterozygosity p53 

Abbreviations

DN

dominant negative

GOF

gain-of-function

HDAC

histone deacetylase

HSF1

heat shock factor 1

HSP

heat shock protein

LOH

loss of heterozygosity

MDM2

mouse double-minute 2

RTK

receptor tyrosine kinases

SAHA

suberoylanilide hydroxamic acid

Notes

Acknowledgements

This work was supported by the Department of Defense grant W81XWH-16-1-0448 (BC151569) and the Carol Baldwin Breast Cancer Research Fund to N. Marchenko.

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of PathologyStony Brook UniversityStony BrookUSA

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