A novel P53/POMC/Gαs/SASH1 autoregulatory feedback loop activates mutated SASH1 to cause pathologic hyperpigmentation

Abstract

Abstractp53‐Transcriptional‐regulated proteins interact with a large number of other signal transduction pathways in the cell, and a number of positive and negative autoregulatory feedback loops act upon the p53 response. P53 directly controls the POMC/α‐MSH productions induced by ultraviolet (UV) and is associated with UV‐independent pathological pigmentation. When identifying the causative gene of dyschromatosis universalis hereditaria (DUH), we found three mutations encoding amino acid substitutions in the gene SAM and SH3 domain containing 1 (SASH1), and SASH1 was associated with guanine nucleotide‐binding protein subunit‐alpha isoforms short (Gαs). However, the pathological gene and pathological mechanism of DUH remain unknown for about 90 years. We demonstrate that SASH1 is physiologically induced by p53 upon UV stimulation and SASH and p53 is reciprocally induced at physiological and pathophysiological conditions. SASH1 is regulated by a novel p53/POMC/α‐MSH/Gαs/SASH1 cascade to mediate melanogenesis. A novel p53/POMC/Gαs/SASH1 autoregulatory positive feedback loop is regulated by SASH1 mutations to induce pathological hyperpigmentation phenotype. Our study demonstrates that a novel p53/POMC/Gαs/SASH1 autoregulatory positive feedback loop is regulated by SASH1 mutations to induce pathological hyperpigmentation phenotype.

p53 regulates ERK1/2/CREB cascade via a novel SASH1/MAP2K2 crosstalk to induce hyperpigmentation

“…Because the ERK1/2 signalling pathway is identified to be responsive to p53‐POMC‐SASH1 cascade, and the ERK1/2 signalling pathway mediates melanogenesis , we sought to address whether mutated SASH1s are induced by p53 and mutations in SASH1 promote biosynthesis of melanogenesis‐specific molecules. Our previous study showed that SASH1 mutations promote the expression of exogenous p53 and more endogenous p53 was induced by Y551D‐SASH1 mutation. Hence, we intend to identify whether p53 could promote mutated SASH1 expression.…”

Hereditary palmoplantar keratodermas. Part I. Non‐syndromic palmoplantar keratodermas: classification, clinical and genetic features

“…Dominant SASH1 mutations are associated with dyschromatosis universalis hereditaria or multiple lentigines phenotypes, characterized by generalized mottled pigmentation and generalized lentiginosis, respectively. [144][145][146][147] Of note, SASH1 has been also identified as a tumour suppressor gene involved in the development of several solid cancers with somatic mutations. [148][149][150]…”

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

“…Finally, immunoprecipitates were washed for three times with PBS and subjected to western blotting. GFP-Tag mouse Ab, Flag-tag mouse mAb, DYKDDDDK-Flag mouse mAb, GAPDH mouse mAb and anti-β-tubulin mouse mAb (Shanghai Abmart, Inc.), anti-Gαs rabbit polyclonal Ab (Gene Tex, Inc.), myc-tag mAb and HA-tag mouse mAb (Shanghai Genomics), SASH1 Rabbit mAb (Bethyl Laboratories, Inc.), TYRP1 (TA99) mouse mAb and melanoma gp100 Rabbit mAb (Abcam), Rab 27a mouse mAb (Abnova) were used for immunoblotting assay as previously described [17,18].…”

“…The melanin staining of paraffin sections obtained from epithelial tissues were performed as our previous descriptions and observed under a light microscope [18].…”

“…The sequences of probes were as indicated in Table 1. Electrophoretic mobility shift assay was performed as described as the protocol provided with LightShift® Chemiluminescent EMSA (20148, Thermo Scientific, Pierce Biotechnology) to detect the bindings of SASH1 with p53 [18].…”