Endoplasmic Reticulum Stress (ERS) is one hallmark of cancer cells: tumor hypoxia, glucose reduction and genome instability all promote accumulation of misfolded proteins in the endoplasmic reticulum. ER stress triggers the Unfolded Protein Response (UPR), a conserved pathway initiated by three ER-resident receptors, IRE1α, PERK, and ATF6, that activate specific and overlapping transcriptional programs aimed to overcome the stress or induce cell death. Accumulating evidence suggest a role for UPR in cancer progression, therefore uncovering functional interactions of this pathway with the oncogenic circuits that drive various tumors may be relevant for therapy. The tumor suppressor p53 is one of the most frequently mutated genes in cancer and missense mutant p53 proteins (mutp53) can acquire powerful oncogenic properties. We recently reported that mutant p53 can modulate the UPR, specifically sustaining activation of the ATF6 branch. This molecular axis may contribute to cancer aggressiveness and resistance to therapy. However, the mechanisms by which mutant p53 can modulate the UPR in cancer cells remained unexplored. In this Thesis, I describe one of the possible mechanisms exploited by mutp53 to sustain ATF6. Using breast, prostate and mammary cancer cell lines, I found that mutant p53 enhances ERS-induced activation of the stress kinase p38MAPK. I also found that inhibition of p38MAPK reduces ERS-induced proteolytic cleavage of ATF6 and its transcriptional activity. These data suggest that p38MAPK may have a pro-survival role in the context of ER stress. Indeed, pharmacologic inhibition of p38MAPK increased the sensitivity to Thapsigargin in cancer cells with mutant p53. Regarding the possible action of p38, I measured the turnover of the active ATF6 fragment, and found that inhibition of p38MAPK induced a perceptible reduction in ATF6f stability. Therefore, one mechanism by which mutp53 can reshape the UPR is by increasing the stability of the active ATF6f protein via enhanced activation of p38MAPK.

The stress-activated kinase p38MAPK contributes to ATF6 activation and resistance to ER stress in cancer cells with mutant p53

DI CRISTINO, FRANCESCA
2022

Abstract

Endoplasmic Reticulum Stress (ERS) is one hallmark of cancer cells: tumor hypoxia, glucose reduction and genome instability all promote accumulation of misfolded proteins in the endoplasmic reticulum. ER stress triggers the Unfolded Protein Response (UPR), a conserved pathway initiated by three ER-resident receptors, IRE1α, PERK, and ATF6, that activate specific and overlapping transcriptional programs aimed to overcome the stress or induce cell death. Accumulating evidence suggest a role for UPR in cancer progression, therefore uncovering functional interactions of this pathway with the oncogenic circuits that drive various tumors may be relevant for therapy. The tumor suppressor p53 is one of the most frequently mutated genes in cancer and missense mutant p53 proteins (mutp53) can acquire powerful oncogenic properties. We recently reported that mutant p53 can modulate the UPR, specifically sustaining activation of the ATF6 branch. This molecular axis may contribute to cancer aggressiveness and resistance to therapy. However, the mechanisms by which mutant p53 can modulate the UPR in cancer cells remained unexplored. In this Thesis, I describe one of the possible mechanisms exploited by mutp53 to sustain ATF6. Using breast, prostate and mammary cancer cell lines, I found that mutant p53 enhances ERS-induced activation of the stress kinase p38MAPK. I also found that inhibition of p38MAPK reduces ERS-induced proteolytic cleavage of ATF6 and its transcriptional activity. These data suggest that p38MAPK may have a pro-survival role in the context of ER stress. Indeed, pharmacologic inhibition of p38MAPK increased the sensitivity to Thapsigargin in cancer cells with mutant p53. Regarding the possible action of p38, I measured the turnover of the active ATF6 fragment, and found that inhibition of p38MAPK induced a perceptible reduction in ATF6f stability. Therefore, one mechanism by which mutp53 can reshape the UPR is by increasing the stability of the active ATF6f protein via enhanced activation of p38MAPK.
COLLAVIN, LICIO
34
2020/2021
Settore BIO/11 - Biologia Molecolare
Università degli Studi di Trieste
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Descrizione: The stress-activated kinase p38MAPK contributes to ATF6 activation and resistance to ER stress in cancer cells with mutant p53
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11368/3030938
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