A gain-of-function mutant p53–HSF1 feed forward circuit governs adaptation of cancer cells to proteotoxic stress

摘要: To overcome proteotoxic stress inherent to malignant transformation, cancer cells induce a range of adaptive mechanisms, with the master transcription factor heat-shock 1 (HSF1)-orchestrated response taking center stage. Here we define novel gain-of-function mutant p53 (mutp53), whereby mutp53-overexpressing acquire superior tolerance stress. mutp53 via constitutive stimulation EGFR and ErbB2 signaling hyperactivates MAPK PI3K cascades, which stabilization phosphoactivation HSF1 on Ser326. Moreover, protein direct interaction activated p-Ser326 facilitates recruitment its specific DNA-binding elements stimulates proteins including Hsp90. In turn, induced Hsp90 stabilizes oncogenic clients EGFR, mutp53, thereby further reinforcing signaling. Thus, initiates feed forward loop that renders more resistant adverse conditions, providing strong survival advantage.