Multiple ETS family transcription factors bind mutant p53 via distinct interaction regions

Area of Science:

• Molecular Biology
• Cancer Research
• Genetics

Background:

• Mutant p53 proteins exhibit gain-of-function activities, but the mechanisms are not fully understood.
• ETS family transcription factors are implicated in mediating p53 functions.
• A comprehensive analysis of p53 interactions across the ETS family is lacking.

Purpose of the Study:

• To investigate the direct binding interactions between mutant p53 and the ETS protein family.
• To identify specific domains and motifs involved in mutant p53-ETS protein binding.
• To explore the functional relevance of these interactions in cancer.

Main Methods:

• Comparative analysis of direct mutant p53 binding to 26 ETS proteins.
• Identification of interaction interfaces, including DNA binding domains and alternate interaction domains.
• Genome-wide mapping of binding sites, exemplified by ERG in prostate cancer cells.
• Correlation analysis of ETS protein expression with p53 mutation status in ovarian cancer.

Main Results:

• All 26 tested ETS proteins bound to mutant p53, with significant variations in binding affinity.
• The ETS DNA binding domain served as a common interface, while a PXXPP motif in an alternate domain was crucial for strong binding.
• The ETS protein ERG was found to mediate mutant p53 DNA binding in prostate cancer cells.
• ETS proteins with strong mutant p53 interaction showed upregulation in p53 mutant ovarian cancer.

Conclusions:

• Multiple ETS family members can mediate gain-of-function mutant p53 activities.
• Specific domains and a novel PXXPP motif are key mediators of mutant p53-ETS interactions.
• These findings provide insights into the mechanisms of mutant p53 function in cancer and identify potential therapeutic targets.