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CRTC3, a sensor and key regulator for melanogenesis, as a tunable therapeutic target for pigmentary disorders

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Abstract
Background: Although CREB phosphorylation is known to be essential in UVB/cAMP-stimulated melanogenesis, CREB null mice did not show identifiable pigmentation phenotypes. Here, we show that CREB-regulated transcription co-activator 3 (CRTC3) quantitatively regulates and orchestrates melanogenesis by directly targeting microphthalmia-associated transcription factor (MITF) and regulating the expression of most key melanogenesis-related genes. Methods: We analyzed CRTC3-null, KRT14-SCF transgenic, and their crossover mice. The molecular basis of CRTC3 effects on pigmentation was investigated by histology, melanin/tyrosinase assay, immunoblotting, shRNA, promoter assay, qRT-PCR, and subcellular localization. These analyses were carried out in primary cultured melanocytes, mouse cell lines, normal human cells, co-cultures, and ex vivo human skin. CRTC/CREB activity screening was performed to identify candidate agents for the regulation of melanogenesis. Results: The coat and skin color of CRTC3-null mice was paler due to a reduction in melanin deposition. Melanogenesis-related genes were reduced in CRTC3-deficient cultured melanocytes and tail skin of CRTC3-null mice. Notably, basal levels of MITF present in CRTC3-null mice were sufficient for melanocytic differentiation/survival. Thus CRTC3-null mice showed a comparable number of epidermal melanocytes compared to control mice. Stem cell factor (SCF) introduction by crossing with KRT14-SCF mice increased epidermal melanocytes and melanin deposition in control and CRTC3-null mice, but the skin color remained still light on the CRTC3-null background. Furthermore, we identified the therapeutic potential of altiratinib to inhibit melanogenesis in human melanocytes and human skin effectively and safely. Conclusion: CRTC3 appears to be a key sensor for melanogenesis and can be used as a reversible and tunable tool for selectively regulating melanogenesis without affecting melanocyte integrity. Thus, CRTC3 can also serve as a screening tool for the discovery of ideal melanogenesis-modulating small molecules.
Author(s)
유한주이하리김기현김민아방승현강영호김우형송영섭장성은
Issued Date
2021
Type
Article
Keyword
cAMP- or UV-stimulated melanogenesisCRTC3/CREBMITFmelanocytes
DOI
10.7150/thno.66378
URI
https://oak.ulsan.ac.kr/handle/2021.oak/8748
https://ulsan-primo.hosted.exlibrisgroup.com/primo-explore/fulldisplay?docid=TN_cdi_proquest_miscellaneous_2601979091&context=PC&vid=ULSAN&lang=ko_KR&search_scope=default_scope&adaptor=primo_central_multiple_fe&tab=default_tab&query=any,contains,CRTC3,%20a%20sensor%20and%20key%20regulator%20for%20melanogenesis,%20as%20a%20tunable%20therapeutic%20target%20for%20pigmentary%20disorders&offset=0&pcAvailability=true
Publisher
Theranostics
Location
오스트레일리아
Language
한국어
ISSN
1838-7640
Citation Volume
11
Citation Number
20
Citation Start Page
9918
Citation End Page
9936
Appears in Collections:
Medicine > Medicine
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