p53 induces the expression of its antagonist p73 Delta N, establishing an autoregulatory feedback loop

Area of Science:

• Molecular Biology
• Cancer Research
• Cellular Regulation

Background:

• The p53 tumor suppressor protein is crucial for activating transcription and inducing cell death.
• p73, a homolog of p53, exists in transactivating (TA) forms that induce growth arrest and apoptosis.
• The p73 gene also produces p73 Delta N variants lacking the N-terminal transactivation domain.

Purpose of the Study:

• To investigate the regulatory relationship between p53 and p73 Delta N.
• To elucidate the mechanism by which p73 Delta N influences p53 activity.
• To understand the role of this interaction in controlling cell death pathways.

Main Methods:

• Cloning and characterization of the promoter regulating p73 Delta N expression.
• Assessing the binding of p73 Delta N proteins to p53-responsive DNA elements.
• Evaluating the impact of p73 Delta N on p53-mediated transcriptional activation and cell death.
• Utilizing transdominant fragments and siRNA to block endogenous p73 Delta N.

Main Results:

• p53 induces the expression of p73 Delta N at both mRNA and protein levels.
• p53 and p73TA activate the p73 Delta N promoter via a specific DNA element.
• p73 Delta N proteins bind to p53-responsive DNA, antagonize p53 transcriptional activity, and inhibit p53-induced cell death.
• A splicing variant, p73 Delta Nalpha, contains a transcriptional repressor domain, enhancing antagonism of p53 when combined with mdm2.
• Blocking endogenous p73 Delta N increases p53-responsive promoter activity.

Conclusions:

• p53-induced expression of p73 Delta N creates a negative feedback loop.
• This feedback loop tightly regulates p53's role in initiating cell death.
• p73 Delta N acts as a crucial inhibitor of p53-mediated apoptosis.