Interferon regulatory factor 1 binding to p300 stimulates DNA-dependent acetylation of p53

Area of Science:

• Molecular Biology
• Cancer Research
• Gene Regulation

Background:

• Interferon regulatory factor 1 (IRF-1) and p53 are key antioncogenic transcription factors.
• Both factors regulate distinct gene sets but converge on p21 gene expression to inhibit tumor formation.

Purpose of the Study:

• To elucidate the mechanism of IRF-1 and p53 synergy at the p21 promoter.
• To investigate the role of p300 coactivator in IRF-1-mediated p53 activation.

Main Methods:

• Investigated IRF-1's DNA-binding-independent function.
• Utilized p300-binding site deletions in IRF-1.
• Employed small peptides mimicking the IRF-1-p300 interface.
• Assessed p53 acetylation and p21 promoter activity using a nonacetylatable p53 mutant (p53-6KR).

Main Results:

• IRF-1 stimulates p21 transcription via p300 binding, independent of its DNA-binding activity.
• IRF-1 binding to p300 allosterically enhances p53-dependent transcription.
• Deletion of p300-binding sites in IRF-1 abrogates p53 acetylation and activity.
• Peptides from the IRF-1-p300 interface promote p53 acetylation and up-regulate p21 expression.
• IRF-1 cannot stimulate the nonacetylatable p53-6KR mutant, confirming the role of acetylation.

Conclusions:

• IRF-1 acts as an allosteric modifier of p53 acetylation at the p21 promoter through its interaction with p300.
• This interaction expands the known p300-p53 interface, revealing a novel mechanism for regulating p53 activity.
• The findings provide insights into the synergistic anti-tumorigenic roles of IRF-1 and p53.