Multifunctional transcriptional coactivator PC4 is a global co-regulator of p53-dependent stress response and gene...

Area of Science:

• Molecular Biology
• Cell Biology
• Genetics

Background:

• Positive coactivator 4 (PC4) is a chromatin-associated protein known to interact with p53.
• The broader regulatory role of PC4 in p53 functions remained largely unexplored.

Purpose of the Study:

• To investigate the comprehensive role of PC4 in p53-mediated gene regulation and cellular processes.
• To explore PC4 as a potential therapeutic target in disease contexts involving p53-dependent cell death.

Main Methods:

• Selective perturbation of the p53-PC4 interaction using a small peptide.
• Over-expression of a p53-binding deficient PC4 mutant.
• Global gene expression profiling (transcriptomics) in A549 cells.
• Assessment of cell death in neuronal cells exposed to amyloid-β.

Main Results:

• Perturbing p53-PC4 interaction abrogated genotoxic stress-induced gene upregulation and reduced apoptosis in A549 cells.
• PC4 mutant recapitulated peptide-induced effects, confirming PC4's role.
• Global gene expression analysis revealed PC4's involvement in multiple p53 pathways, including the Hippo pathway.
• Peptide treatment reduced amyloid-β-induced death in neuronal cells.

Conclusions:

• PC4 acts as a global co-regulator of p53.
• PC4 is a promising therapeutic target for diseases where p53-dependent cell death is critical, such as neurodegenerative conditions.