p53 regulates <scp>ERK</scp>1/2/<scp>CREB</scp> cascade <i>via</i> a novel <scp>SASH</scp>1/<scp>MAP</scp>2K2 crosstalk to induce hyperpigmentation

Zhou, Ding’an; Kuang, Zhongshu; Zeng, Xing; Wang, Ke; Ma, Jiangshu; Luo, Huangchao; Chen, Mei; Li, Yán; Zeng, Jiawei; Li, Shu; Luan, Fu-Jun; He, Yong; Dai, Hongying; Liu, Beizhong; Li, Hui; He, Lin; Xing, Qinghe

doi:10.1111/jcmm.13168

Cited by 18 publications

(43 citation statements)

References 40 publications

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“…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]…”

Section: Hyperkeratosis-hyperpigmentation Syndromementioning

confidence: 99%

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

Guerra

Castori

Didona

et al. 2018

Acad Dermatol Venereol

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The term palmoplantar keratoderma (PPK) indicates any form of persistent thickening of the epidermis of palms and soles and includes genetic as well as acquired conditions. We review the nosology of hereditary PPKs that comprise an increasing number of entities with different prognoses, and a multitude of associated cutaneous and extracutaneous features. On the basis of the phenotypic consequences of the underlying genetic defect, hereditary PPKs may be divided into the following: (i) non-syndromic, isolated PPKs, which are characterized by a unique or predominant palmoplantar involvement; (ii) non-syndromic PPKs with additional distinctive cutaneous and adnexal manifestations, here named complex PPKs; (iii) syndromic PPKs, in which PPK is associated with specific extracutaneous manifestations. To date, the diagnosis of the different hereditary PPKs is based mainly on clinical history and features combined with histopathological findings. In recent years, the exponentially increasing use of next-generation sequencing technologies has led to the identification of several novel disease genes, and thus substantially contributed to elucidate the molecular basis of such a heterogeneous group of disorders. Here, we focus on hereditary non-syndromic isolated and complex PPKs. Syndromic PPKs are reviewed in the second part of this 2-part article, where other well-defined genetic diseases, which may present PPK among their phenotypic manifestations, are also listed and diagnostic and therapeutic approaches for PPKs are summarized.

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Section: Hyperkeratosis-hyperpigmentation Syndromementioning

confidence: 99%

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

Guerra

Castori

Didona

et al. 2018

Acad Dermatol Venereol

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“…Feedback loops of p53 and p53-responsive genes provide a means to connect the p53 pathway with other signal transduction pathways and coordinate the cellular signals for growth and division [30]. Our findings suggest that SASH1 serves as a "Hinge" to connect p53/POMC/α-MSH pathway with MC1R/Gαs/cAMP/ PKA cascade to form an autoregulatory p53/POMC/Gαs/SASH1 circuit to mediate the melanogenesis process [18,31].…”

Section: Increased Production Of Melanogenic Components and Heterogenmentioning

confidence: 85%

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

Zhou¹,

Zeng²,

Zeng³

et al. 2019

Molecular Medicine

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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.

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“…In an interesting finding, SYT4 interacted with ERK and positively regulated p‐ERK expression. The ERK signalling pathway may negatively affect the melanogenesis induced by the p53‐POMC‐MC1R signalling cascade to enhance the phosphorylation levels of ERK1/2 and CREB . CREB activates the transcription of MITF, which consequently triggers the transcription of the downstream melanogenic genes TYR, TYRP1, and DCT, causing increases in the melanin content.…”

Section: Discussionmentioning

confidence: 99%

Synaptotagmin‐4 promotes dendrite extension and melanogenesis in alpaca melanocytes by regulating Ca²⁺ influx via TRPM1 channels

Jia

Jiao

et al. 2019

Cell Biochemistry & Function

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Synaptotagmin-4 (SYT4) is a membrane protein that regulates membrane traffic in neurons in a calcium-dependent or calcium-independent manner. In melanocytes, the intracellular free calcium ion (Ca 2+ ) may be important for dendrite growth and melanogenesis. Mammalian melanocytes originating from neural crest cells produce melanins. Therefore, we predicted that SYT4 might play a role in melanogenesis and the dendrite morphology of melanocytes. To investigate whether SYT4 is involved in melanocyte physiology, SYT4 was overexpressed in alpaca melanocytes and B16-F10 cells. The results showed that SYT4 overexpression resulted in a phenotype consistent with melanogenesis and dendrite extension. At the molecular level, SYT4interacted with extracellular regulated MAP kinase (ERK) to decrease p-ERK activity, which negatively regulated CREB expression. Furthermore, cyclic AMP-responsive element-binding protein (CREB) was upregulated and caused the downregulation of the expression of melanogenic regulatory proteins, including microphthalmia-associated transcription factor (MITF), tyrosinase (TYR), tyrosinase-related protein-1 (TYRP1), dopachrome tautomerase (DCT), and transient receptor potential melastatin 1 (TRPM1). Intracellular free Ca 2+ promoted the upregulation of calcium/calmodulin dependent protein kinase IV (CAMK4) expression, which phosphorylated CREB (p-CREB). In turn, p-CREB participated in the transcription of MITF. These results demonstrated that SYT4 promoted melanogenesis through dendrite extension and tyrosinase activity, during which the regulation of Ca 2+ influx via the TRPM1 channel was a key factor.Significance of the study: Intracellular Ca 2+ is important for the function and survival of melanocytes and melanoma cells. SYT4 stimulated melanogenesis through calcium.These results provide evidence that SYT4 regulates Ca 2+ influx through TRPM1 to cause melanogenesis and axonal elongation in alpaca melanocytes and further suggesting that the growth and metastasis of melanoma is controlled by the inhibited expression of SYT4 in melanoma cells.

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

Cited by 18 publications

References 40 publications

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

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

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

Synaptotagmin‐4 promotes dendrite extension and melanogenesis in alpaca melanocytes by regulating Ca²⁺ influx via TRPM1 channels

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

Cited by 18 publications

References 40 publications

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

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

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

Synaptotagmin‐4 promotes dendrite extension and melanogenesis in alpaca melanocytes by regulating Ca2+ influx via TRPM1 channels

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Product

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Synaptotagmin‐4 promotes dendrite extension and melanogenesis in alpaca melanocytes by regulating Ca²⁺ influx via TRPM1 channels