Abstract
To overcome proteotoxic stress inherent to malignant transformation, cancer cells induce a range of adaptive mechanisms, with the master transcription factor heat-shock factor 1 (HSF1)-orchestrated response taking center stage. Here we define a novel gain-of-function of mutant p53 (mutp53), whereby mutp53-overexpressing cancer cells acquire superior tolerance to proteotoxic stress. mutp53 via constitutive stimulation of EGFR and ErbB2 signaling hyperactivates the MAPK and PI3K cascades, which induce stabilization and phosphoactivation of HSF1 on Ser326. Moreover, mutp53 protein via direct interaction with activated p-Ser326 HSF1 facilitates HSF1 recruitment to its specific DNA-binding elements and stimulates transcription of heat-shock proteins including Hsp90. In turn, induced Hsp90 stabilizes its oncogenic clients including EGFR, ErbB2 and mutp53, thereby further reinforcing oncogenic signaling. Thus, mutp53 initiates a feed forward loop that renders cancer cells more resistant to adverse conditions, providing a strong survival advantage.
Highlights
We identify a novel gain-of-function of mutp[53] as a promoter of HSF1 activity
Guarding the proteome against misfolding and aggregation induced by proteotoxic stress due to heat, ROS, hypoxia, acidosis, DNA damage and aneuploidy, several stressinduced heat-shock proteins (HSPs) including Hsp[90], Hsp[70] and Hsp[27] are essential in guiding proper refolding of stress-misfolded ‘client’ polypeptides
We show that mutp[53], via augmented Epidermal Growth Factor Receptor (EGFR and/or ErbB2) signaling, hyperactivates the MAPK and PI3K cascades, which lead to stabilization, phosphorylation and transcriptional activation of HSF1
Summary
We identify a novel gain-of-function of mutp[53] as a promoter of HSF1 activity. We show that mutp[53], via augmented Epidermal Growth Factor Receptor (EGFR and/or ErbB2) signaling, hyperactivates the MAPK and PI3K cascades, which lead to stabilization, phosphorylation and transcriptional activation of HSF1. By direct protein–protein interaction with activated HSF1, mutp[53] facilitates recruitment of HSF1 to its target promoters and stimulates HSF1-transcription program, including HSP transcription. HSPs stabilize their oncogenic clients including EGFR, ErbB2 and mutp[53], thereby further reinforcing tumorigenesis. Mutp[53] initiates a regulatory feed forward loop that renders cancer cells resistant to proteotoxic stress, providing a distinct survival advantage
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