Journal Article

Targeting phosphorylation circuits on CREB and CRTCs as the strategy to prevent acquired skin hyperpigmentation

Lee, Seung Wha, Hwang, Bang Yeon, Baek, Seung Tae, An, Hyun Jin, Lee, Jae Duk, Kim, Jun Gu, Han, Sang-Bae, Yun, Cheng-Yong, Jung, Jae-Kyung, Kim, Youngoo, Kim, Song-Hee

2024

Overview

The cAMP response element-binding protein (CREB) and CREB-regulated transcription coactivators (CRTCs) cooperate in the transcriptional activation of microphthalmia-associated transcription factor subtype M (MITF-M) that is a master regulator in the biogenesis, pigmentation and transfer of melanosomes at epidermal melanocytes. Here, we propose the targeting of phosphorylation circuits on CREB and CRTCs in the expression of MITF-M as the rationale to prevent skin hyperpigmentation by elucidating the inhibitory activity and mechanism of yakuchinone A (Yaku A) on facultative melanogenesis. We employed human epidermal melanocyte cell, mouse skin, and mouse melanoma cell, and applied Western blotting, reverse transcription-polymerase chain reaction, immunoprecipitation and confocal microscopy to conduct this study. This study suggested that α-melanocyte stimulating hormone (α-MSH)-induced melanogenic programs could switch on the axis of protein kinase A-salt inducible kinases (PKA-SIKs) rather than that of PKA-AMP activated protein kinase (PKA-AMPK) during the dephosphorylation of CRTCs in the expression of MITF-M. SIK inhibitors rather than AMPK inhibitors stimulated melanin production in melanocyte cultures in the absence of extracellular melanogenic stimuli, wherein SIK inhibitors increased the dephosphorylation of CRTCs but bypassed the phosphorylation of CREB for the expression of MITF-M. Treatment with Yaku A prevented ultraviolet B (UV-B)-irradiated skin hyperpigmentation in mice and inhibited melanin production in α-MSH- or SIK inhibitor-activated melanocyte cultures. Mechanistically, Yaku A suppressed the expression of MITF-M via dually targeting the i) cAMP-dependent dissociation of PKA holoenzyme at the upstream from PKA-catalyzed phosphorylation of CREB coupled with PKA-SIKs axis-mediated dephosphorylation of CRTCs in α-MSH-induced melanogenic programs, and ii) nuclear import of CRTCs after SIK inhibitor-induced dephosphorylation of CRTCs. Taken together, the targeting phosphorylation circuits on CREB and CRTCs in the expression of MITF-M could be a suitable strategy to prevent pigmentary disorders in the skin.

• Publisher: Ivyspring International Publisher Pty Ltd,Ivyspring International Publisher
• Subject: Adenosine / alpha-MSH - metabolism / AMP-activated protein kinase / AMP-Activated Protein Kinases - metabolism / Animals / Antibiotics / Cell Line, Tumor / Circuits / Confocal microscopy / Cyclic AMP response element-binding protein / Cyclic AMP Response Element-Binding Protein - metabolism / Dephosphorylation / FDA approval / Hormones / Humans / Hyperpigmentation / Hyperpigmentation - metabolism / Immunoprecipitation / Inhibitors / Kinases / Laboratory animals / Melanin / Melanins - metabolism / Melanocytes / Melanocytes - metabolism / Melanoma / Melanosomes / Mice / Microphthalmia-associated transcription factor / Microphthalmia-Associated Transcription Factor - genetics / Microphthalmia-Associated Transcription Factor - metabolism / Nuclear transport / Phosphorylation / Pigmentation / Polymerase chain reaction / Protein kinase A / Proteins / Research Paper / Reverse transcription / Skin / Transcription activation / Transcription factors / Ultraviolet radiation / Western blotting