A Mouse Homolog of a Human TP53 Germline Mutation Reveals a Lipolytic Activity of p53

• Published in: Cell reports (Cambridge) 2020-01, Vol.30 (3), p.783-792.e5
• Main Authors: Kang, Ju-Gyeong, Lago, Cory U., Lee, Ji-Eun, Park, Ji-Hoon, Donnelly, Matthew P., Starost, Matthew F., Liu, Chengyu, Kwon, Jaeyul, Noguchi, Audrey C., Ge, Kai, Wang, Ping-yuan, Hwang, Paul M.
• Format: Article
• Language: English
• Subjects: 3T3-L1 Cells; Adipocytes - metabolism; Adipose Tissue, White - pathology; ADRB3; Animals; Base Sequence; cancer; fat; Fatty Acids - blood; Gene Expression Regulation; Germ-Line Mutation - genetics; Homozygote; Humans; Li-Fraumeni syndrome; Li-Fraumeni Syndrome - genetics; lipolysis; Lipolysis - genetics; Metabolomics; Mice; Mice, Inbred C57BL; mouse model; Phenotype; Principal Component Analysis; Receptors, Adrenergic, beta-3 - genetics; Sequence Homology, Amino Acid; Signal Transduction; TP53 mutation; Tumor Suppressor Protein p53 - genetics
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2019.12.074

The physiological effects of the many germline mutations of TP53, encoding the tumor suppressor protein p53, are poorly understood. Here we report generating a p53 R178C knockin mouse modeling the human TP53 R181C mutation, which is notable for its prevalence and prior molecular characterization. Consistent with its weak cancer penetrance in humans, homozygous p53178C/C mice show a modest increase in tumorigenesis but, surprisingly, are lean with decreased body fat content. They display evidence of increased lipolysis and upregulation of fatty acid metabolism in their inguinal white adipose tissue (iWAT). Gene expression and chromatin immunoprecipitation sequencing (ChIP-seq) analyses show that the mutant p53 bound and transactivated Beta-3-Adrenergic Receptor (ADRB3), a gene that is known to promote lipolysis and is associated with obesity. This study reveals that a germline mutation of p53 can affect fat metabolism, which has been implicated in cancer development. [Display omitted] •Mouse homolog of a TP53 germline mutation reveals a metabolic phenotype•Mutant p53 R178C differentially retains wild-type p53 activity•ChIP-seq analysis identifies adrenergic receptor ADRB3 as a p53 target gene•p53 R178C promotes lipolysis in adipocytes by increased ADRB3 signaling Knockin of the mouse homolog of a human TP53 germline mutation known to cause Li-Fraumeni syndrome, a cancer predisposition disorder, results in a mouse model characterized by lower body fat content. Kang et al. show that enhancing transactivation of the lipolytic gene ADRB3 by mutant p53 contributes to this phenotype.