Abstract
Paired box gene 3 (Pax3) and cAMP responsive element-binding protein (CREB) directly interact with the cis-acting elements on the promoter of microphthalmia-associated transcription factor isoform M (MITF-M) for transcriptional activation in the melanogenic process. Tyrosinase (Tyro) is a target gene of MITF-M, and functions as a key enzyme in melanin biosynthesis. Tetrahydroquinoline carboxamide (THQC) was previously screened as an antimelanogenic candidate. In the current study, we evaluated the antimelanogenic activity of THQC in vivo and elucidated a possible mechanism. Topical treatment with THQC mitigated ultraviolet B (UVB)-induced skin pigmentation in guinea pig with decreased messenger RNA (mRNA) and protein levels of melanogenic genes such as MITF-M and Tyro. Moreover, THQC inhibited cAMP-induced melanin production in α-melanocyte-stimulating hormone (α-MSH)- or histamine-activated B16-F0 cells, in which it suppressed the expression of the MITF-M gene at the promoter level. As a mechanism, THQC normalized the protein levels of Pax3, a transcriptional activator of the MITF-M gene, in UVB-exposed and pigmented skin, as well as in α-MSH-activated B16-F0 culture. However, THQC did not affect UVB- or α-MSH-induced phosphorylation (activation) of CREB. The results suggest that suppression of the Pax3–MITF-M axis might be a potential strategy in the treatment of skin pigmentary disorders that are at high risk under UVB radiation.
Highlights
Skin hyperpigmentation is characterized by an excess increase in the number of melanocytes, melanosome biogenesis with melanin pigmentation in melanocytes, and melanosome transfer to keratinocytes [1]
The results suggest suppression of the Paired box gene 3 (Pax3)–Microphthalmia-associated transcription factor isoform M (MITF-M) axis as a potential strategy in the treatment of skin pigmentary disorders that are at high risk under ultraviolet B (UVB) radiation
We first carried out UVB-induced skin pigmentation to understand the antimelanogenic activity of Tetrahydroquinoline carboxamide (THQC) in vivo
Summary
Skin hyperpigmentation (pigmented spot) is characterized by an excess increase in the number of melanocytes, melanosome biogenesis with melanin pigmentation in melanocytes, and melanosome transfer to keratinocytes [1]. Solar ultraviolet B (UVB) radiation is a major factor governing acquired pigmentation in the skin [2,3]. Melanogenic hormones are produced and secreted from epidermal keratinocytes, where UVB radiation stimulates the expression of the pro-opiomelanocortin (POMC) gene [4,5]. Following enzymatic processing of POMC polypeptide, α-melanocyte-stimulating hormone (α-MSH) is produced in keratinocytes [6]. Α-MSH binds to melanocortin 1 receptor (MC1R) on the membrane surface of melanocytes in the epidermal/dermal border of skin, which mediates signaling cascade for melanosome biogenesis with melanin pigmentation [7,8]. Black-brownish eumelanin and yellow-reddish pheomelanin are produced in the melanosome, an organelle of melanocytes [10,11]. Melanosomes are delivered to keratinocytes in the overlaying epidermis for skin pigmentation [13]
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