Interplay between Endoplasmic Reticulum (ER) Stress and Autophagy Induces Mutant p53H273 Degradation.

Biomolecules
A GarufiG D'Orazi

Abstract

The unfolded protein response (UPR) is an adaptive response to intrinsic and external stressors, and it is mainly activated by the accumulation of misfolded proteins at the endoplasmic reticulum (ER) lumen producing ER stress. The UPR signaling network is interconnected with autophagy, the proteolytic machinery specifically devoted to clearing misfolded proteins in order to survive bioenergetic stress and/or induce cell death. Oncosuppressor TP53 may undergo inactivation following missense mutations within the DNA-binding domain (DBD), and mutant p53 (mutp53) proteins may acquire a misfolded conformation, often due to the loss of the DBD-bound zinc ion, leading to accumulation of hyperstable mutp53 proteins that correlates with more aggressive tumors, resistance to therapies, and poorer outcomes. We previously showed that zinc supplementation induces mutp53 protein degradation by autophagy. Here, we show that mutp53 (i.e., Arg273) degradation following zinc supplementation is correlated with activation of ER stress and of the IRE1α/XBPI arm of the UPR. ER stress inhibition with chemical chaperone 4-phenyl butyrate (PBA) impaired mutp53 downregulation, which is similar to IRE1α/XBPI specific inhibition, reducing cancer cell deat...Continue Reading

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Citations

Jul 2, 2020·Journal of Experimental & Clinical Cancer Research : CR·Alessia GarufiGabriella D'Orazi
Oct 19, 2020·Cellular and Molecular Life Sciences : CMLS·Gabriella D'OraziMara Cirone
Feb 7, 2021·Biomolecules·Gabriella D'Orazi
Mar 12, 2021·Journal of Cellular Physiology·Yuping LuoMin Li

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Methods Mentioned

BETA
Assay
light microscopy
Fluorescence
electrophoresis

Software Mentioned

ModFit LT
ImageJ NIH )

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