Domain-specific p53 mutants activate EGFR by distinct mechanisms exposing tissue-independent therapeutic...

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Mutations in TP53 can promote cancer by losing tumor suppression and gaining pro-carcinogenic functions.
• Gain-of-function mutations in TP53 are increasingly recognized for their roles in tumorigenesis.

Purpose of the Study:

• To investigate the previously unrecognized molecular mechanisms by which TP53 mutants activate epidermal growth factor receptor (EGFR) signaling.
• To elucidate the distinct roles of DNA-binding domain (DBD) and transactivation domain (TAD) TP53 mutants in EGFR signaling.

Main Methods:

• Analysis of cellular localization of TP53 mutants and EGFR.
• Gene expression profiling in response to different TP53 mutants.
• Investigation of protein-protein interactions involving TP53 mutants, EGFR, AKT, DDX31, and SHP1.

Main Results:

• TP53 DBD and TAD mutants differentially localize and affect EGFR stability in cytosolic and nuclear compartments.
• TAD mutants enhance EGFR signaling via AKT and DDX31 in the cytosol.
• DBD mutants maintain nuclear EGFR activity by inhibiting SHP1, leading to c-Myc and Cyclin D1 upregulation.

Conclusions:

• Gain-of-function TP53 mutants activate pro-carcinogenic EGFR signaling through distinct mechanisms dependent on the affected domain (DBD or TAD).
• These findings reveal novel protein complexes formed by TP53 mutants that enhance EGFR signaling, presenting potential therapeutic targets.