A role of cytoplasmic p53 in the regulation of metabolism shown by bat-mimicking p53 NLS mutant mice
Jack D. Sanford,
Aiwen Jin,
Gabriella A. Grois,
Yanping Zhang
Affiliations
Jack D. Sanford
Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA; Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA
Aiwen Jin
Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA
Gabriella A. Grois
Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA
Yanping Zhang
Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA; Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA; Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA; Corresponding author
Summary: The transcription factor p53 suppresses tumorigenesis via a wide-ranging, concerted set of functions. Although several studies have identified cytoplasmic, transcription-independent functions of p53, the biological relevance of these activities has not been fully elucidated, particularly in vivo. Here, we generated a mouse model with a p53K316P mutation, which mimics a naturally occurring p53 nuclear localization signal (NLS) change observed in bat species. We find that the p53K316P mutation increases cytoplasmic localization of p53 and promotes a pleiotropic metabolic phenotype that includes increased adiposity, increased de novo lipogenesis, and decreased lactate generation. Mechanistic studies show that, independent of its transactivation function, p53K316P interacts with lactate dehydrogenase B (LDHB) and alters the composition and enzymatic activities of LDH complex favoring pyruvate generation and hindering lactate production. Overall, the study identifies a role for cytoplasmic p53 in the regulation of metabolism that favors energy generation and storage.
