Abstract
p53‐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.
Highlights
The skin pigmentation is originated from the synthesis of melanin in the melanocytes, followed by distribution and transport of pigment granules to neighbouring keratinocytes [1]
We demonstrate that the reciprocal induction of p53 and SAM and SH3 domain containing 1 (SASH1) promotes cutaneous pigmentation by an autoregulatory p53/POMC/aMSH/guanine nucleotide-binding protein subunit-alpha isoforms short (Gas)/SASH1 loop in the skin
SASH1 mutations-mediated-POMC up-regulation causes the pathological hyperpigmentations of DUHaffected individuals
Summary
The skin pigmentation is originated from the synthesis of melanin in the melanocytes, followed by distribution and transport of pigment granules to neighbouring keratinocytes [1]. Variations in the coding region of the melanocortin-1-receptor (MC1R) are important for tanning and pigmentation in human beings. MC1R is a G protein-coupled receptor (GPCR) that is preferentially expressed in epidermal melanocytes [2] and is activated by its ligand a-melanocyte-stimulating hormone (a-MSH), a propigmentation hormone which is produced and secreted by both keratinocytes and melanocytes in the skin following UV. Normal synthesis of a-MSH and ACTH is an important determinant of constitutive human pigmentation and the cutaneous response to UV [2]. MC1R regulates the amount and type of pigment production and is a major determinant of skin phototype,.
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