A Novel P53/POMC/Gas/SASH1 Autoregulatory Feedback Loop and Pathologic Hyperpigmentation

P53-regulated proteins in transcriptional level are associated with many signal transduction pathways and p53 plays a pivotal role in a number of positive and negative autoregulatory feedback loops. Although POMC/α-MSH productions induced by ultraviolet (UV) are directly mediated by p53, p53 is related to UV-independent pathological pigmentation. In the process of identifying the causative gene of dyschromatosis universalis hereditaria (DUH), three mutations encoding amino acid substitutions were found in the gene SAM and SH3 domain containing 1 (SASH1). SASH1 was identified to interact with guanine nucleotide-binding protein subunit-alpha isoforms short (Gαs). However, for about 90 years, the pathological gene and the pathological mechanism of DUH are unclear. Our study indicates that SASH1 is physiologically medicated by p53 upon UV stimulation and a reciprocal SASH-p53 inducement is existed physiologically and pathophysiologically. A novel p53/POMC/α-MSH/Gαs/SASH1 signal cascade regulates SASH1 to foster melanogenesis. SASH1 mutations control a novel p53/POMC/Gαs/SASH1 autoregulatory positive feedback loop to promote pathological hyperpigmentation phenotype in DUH-affected individuals. Our work illustrates a novel p53/POMC/Gαs/SASH1 autoregulatory positive feedback loop that is mediated by SASH1 mutations to foster pathological hyperpigmentation phenotype