The role of p53 in regulating chaperone-mediated autophagy

University Of Pennsylvania, Philadelphia PA

Investigators

Abstract

ABSTRACT This proposal aims to define the role of p53 in regulating chaperone-mediate autophagy (CMA) and the consequences of this regulation on tumorigenesis. p53 holds the distinction of being the most frequently mutated gene in human tumors. Inactivation of p53 is essential not only for the initiation of a remarkably wide range of tumors but also for their continued survival and proliferation. Thus, understanding the mechanism by which p53 suppresses tumorigenesis is a central objective in cancer biology. p53 is known to induce apoptosis, cell cycle arrest, and senescence. However, emerging evidence indicates that these canonical activities may not fully account for p53-mediated tumor suppression, underscoring the need to identify and characterize additional cellular processes that are regulated by p53. CMA is a highly selective form of autophagy. Unlike macroautophagy, which delivers proteins and organelles in bulk to the lysosome for degradation, CMA targets a subset of cytoplasmic proteins individually. This selectivity permits CMA to regulate intracellular processes. CMA is demonstrated only in vertebrates, and it might have evolved later during evolution to modulate increasingly elaborate biological processes. However, both the regulation and functions of CMA remain unclear. We recently found that CMA governs the balance between self-renewal and differentiation of embryonic stem cells. Our preliminary results further suggested that p53 may be an important activator for CMA. Through this activation, p53 inhibits key enzymes in the tricarboxylic acid (TCA) cycle, a central metabolic hub essential for oncogenic growth. These findings reveal previously unrecognized connections among p53, CMA, and metabolism that impact tumorigenesis. Our central hypothesis is that p53 is an important regulator of CMA, and p53-mediated CMA activation and metabolic regulation contribute to tumor suppression. We propose three specific aims: (1) Elucidate the function of p53 in regulating CMA, (2) Define the molecular mechanisms by which p53 regulates CMA, and (3) Determine the role of p53-mediated CMA activation and metabolic regulation in tumor suppression. The proposed studies will reveal a fundamental component of p53 biological function. They will also likely suggest new targets for cancer therapy.