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 death. Knockdown of mutp53 failed to induce UPR/autophagy activation indicating that the effect of zinc on mutp53 folding was likely the key event occurring in ER stress activation. Recently discovered small molecules targeting components of the UPR show promise as a novel anticancer therapeutic intervention. However, our findings showing UPR activation during mutp53 degradation indicate that caution is necessary in the design of therapies that inhibit UPR components.

Interplay between endoplasmic reticulum (ER) stress and autophagy induces mutant p53H273 degradation / Garufi, Alessia; Federici, Giulia; Gilardini Montani, Maria Saveria; Crispini, Alessandra; Cirone, Mara; D'Orazi, Gabriella. - In: BIOMOLECULES. - ISSN 2218-273X. - 10:3(2020). [10.3390/biom10030392]

Interplay between endoplasmic reticulum (ER) stress and autophagy induces mutant p53H273 degradation

Gilardini Montani, Maria Saveria;Cirone, Mara;
2020

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 death. Knockdown of mutp53 failed to induce UPR/autophagy activation indicating that the effect of zinc on mutp53 folding was likely the key event occurring in ER stress activation. Recently discovered small molecules targeting components of the UPR show promise as a novel anticancer therapeutic intervention. However, our findings showing UPR activation during mutp53 degradation indicate that caution is necessary in the design of therapies that inhibit UPR components.
2020
4-PBA; IRE1α/XBP1; ST-083010; autophagy; cancer therapy; endoplasmic reticulum (ER) stress; mutp53H273; p53; zinc supplementation
01 Pubblicazione su rivista::01a Articolo in rivista
Interplay between endoplasmic reticulum (ER) stress and autophagy induces mutant p53H273 degradation / Garufi, Alessia; Federici, Giulia; Gilardini Montani, Maria Saveria; Crispini, Alessandra; Cirone, Mara; D'Orazi, Gabriella. - In: BIOMOLECULES. - ISSN 2218-273X. - 10:3(2020). [10.3390/biom10030392]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1374142
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