TAp63γ is the primary isoform of TP63 for tumor suppression but not development.

TP63 is expressed as TAp63 and ΔNp63 from the P1 and P2 promoters, respectively. While TAp63 and ΔNp63 are expressed as three TAp63α/β/γ and ΔNp63α/β/γ due to alternative splicing, only p63α (TA and ΔN) and p63γ (TA and ΔN) proteins are found to be detectable and likely to be responsible for p63-dependent activity. Previous studies implied and/or demonstrated that TAp63α, which contains an N-terminal activation domain conserved in p53, functions as a tumor suppressor by regulating an array of genes for growth suppression. By contrast, ΔNp63α, which also contains an N-terminal activation domain but is different from that in TAp63, regulates a unique set of genes and functions as a master regulator for development of epidermis and other stratified epithelial tissues. However, the biological function of p63γ is largely unexplored. To explore this, we generated a mouse model in that exon 10', a coding exon specific for p63γ, was deleted by CRISPR-cas9. We showed that mice deficient in p63γ are viable and futile, which is different from mice deficient in total TP63 or p63α. Like TAp63-deficient mice, p63γ-deficient mice have a short lifespan and are prone to spontanenous tumors. Additionally, loss of p63γ shortens the lifespan of tumor-free mice potentially via increased cellular senescence. Moreover, mice deficient in p63γ are prone to chronic inflammation in multiple organs and liver steatosis potentially via altered lipid metabolism. Single-cell RNA-seq revealed that loss of p63γ increases the expression of SCD1, a rate-limiting enzyme for synthesis of monounsaturated fatty acids, leading to altered lipid homeostasis. Together, our data indicate that TP63γ is the primary isoform of TP63 for tumor suppression but not development by maintaining normal inflammatory response and lipid homeostasis.