Abstract 843: Isoform-specific disruption of the TP73 gene reveals a critical role for TAp73gamma in tumorigenesis and obesity via leptin

Abstract TP73, a member of the p53 family, is expressed as TAp73 and ΔNp73 along with multiple C-terminal isoforms (α-η). Interestingly, TAp73 is shown to have opposing functions in tumorigenesis but the mechanism remains unclear. Here, we showed that deletion of exon 11 (E11) switches p73α to p73γ, the latter of which has oncogenic activities. Moreover, E11-deficient mice phenocopies Trp73-deficient mice with short lifespan, infertility, chronic inflammation and tumor incidence, indicating that p73γ cannot compensate p73α for tumor suppression and fertility. E11-deficient mice were also prone to obesity and B-cell lymphomas, indicating a unique role of p73γ in lipid metabolism and tumorigenesis. Mechanistically, we showed that Leptin, a pleiotropic adipocytokine, was highly induced by p73γ and necessary for p73γ-mediated oncogenic activity. Importantly, p73α-γ isoform switch was detected in dog lymphomas and human prostate carcinomas along with elevated expression of Leptin. Our study indicates that the p73γ-Leptin pathway promotes tumorigenesis and alters lipid metabolism. Citation Format: Xiangmudong Kong, Wenqiang Sun, Jin Zhang, xinbin Chen. Isoform-specific disruption of the TP73 gene reveals a critical role for TAp73gamma in tumorigenesis and obesity via leptin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 843.