CRTC3, a sensor and key regulator for melanogenesis, as a tunable therapeutic target for pigmentary disorders
| Autor: | Sung Eun Chang, Youngsup Song, Seunghyun Bang, Ha-Ri Lee, Min-Ah Kim, Ki-Hyun Kim, Young-Ho Kang, Woo-hyung Kim, Hanju Yoo |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Male
Transgene Tyrosinase Primary Cell Culture Medicine (miscellaneous) Gene Expression Stem cell factor Human skin Skin Pigmentation Melanocyte CREB CRTC3/CREB Cell Line Melanin Mice medicine Animals Humans Phosphorylation Pharmacology Toxicology and Pharmaceutics (miscellaneous) Melanoma Skin Melanins Mice Knockout MITF Microphthalmia-Associated Transcription Factor biology integumentary system Chemistry Keratin-14 Microphthalmia-associated transcription factor Cell biology cAMP- or UV-stimulated melanogenesis Gene Expression Regulation Neoplastic Mice Inbred C57BL melanocytes medicine.anatomical_structure biology.protein Female Epidermis Research Paper Transcription Factors |
| Zdroj: | Theranostics |
| ISSN: | 1838-7640 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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