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

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.

The highest-elevation frog provides insights into mechanisms and evolution of defenses against high UV radiation

“…TYR is up-regulated gradually during UV exposure and works with up-regulated SLC45A2 to induce melanin generation in melanosomes. This process may also trigger observed up-regulation of the TC-NER master organizing protein gene ERCC6 [involved in DNA repair ( 45 )] and CRTC3 [involved in cell cycle regulation and melanogenesis ( 46 )] ( SI Appendix , Fig. S16 ).…”

Inflammatory response: The target for treating hyperpigmentation during the repair of a burn wound

“…SIK, which is suppressed after phosphorylation, releases more unphosphorylated CREB-regulated transcription coactivator (CRCT), which shuttles into the nucleus and binds to the already activated CREB. This complex cooperatively activates the promotor of MITF (33)(34)(35).…”

The Universal Role of Adaptive Transcription in Health and Disease

“…The skin has to undergo complex adaptations in response to external and internal stressors, including melanogenesis after UV exposure or wound healing after injury. Melanogenesis in mice is regulated by the CREB-associated protein CRTC [103,104]. SRF in keratinocytes is involved in correct skin development [105].…”