Abstract
Acetylcholinesterase (AChE) hydrolyzes the neurotransmitter acetylcholine in neurons. However, AChE has been proposed to also have nonneuronal functions in different cell types. Here, we report that AChE is expressed in melanocytes and melanoma cells, and that the tetrameric (G4) form is the major AChE isoform in these cells. During melanogenesis of B16F10 murine melanoma cells, AChE levels decreased markedly. The differentiation of melanoma cells led to (i) an increase in melanin and tyrosinase, (ii) a change in intracellular cAMP levels, and (iii) a decrease in microphthalmia-associated transcription factor (MITF). We hypothesized that the regulation of AChE during melanogenesis is mediated by two transcription factors: cAMP-response element-binding protein (CREB) and MITF. In melanoma cells, exogenous cAMP suppressed AChE expression and the promoter activity of the ACHE gene. This suppression was mediated by a cAMP-response element (CRE) located on the ACHE promoter, as mutation of CRE relieved the suppression. In melanoma, MITF overexpression induced ACHE transcription, and mutation of an E-box site in human ACHE promoter blocked this induction. An AChE inhibitor greatly enhanced acetylcholine-mediated responses of melanogenic gene expression levels in vitro; however, this enhancement was not observed in the presence of agonists of the muscarinic acetylcholine receptor. These results indicate that ACHE transcription is regulated by cAMP-dependent signaling during melanogenesis of B16F10 cells, and the effect of this enzyme on melanin production suggests that it has a potential role in skin pigmentation.
Highlights
Melanogenesis is a process of melanin production in melanocyte or melanoma cells
The binding of ␣-MSH to melanocortin 1 receptor (MC1R) increases adenylyl cyclase activity, resulting in cAMP-induced transcription of the master transcriptional factor microphthalmia-associated transcription factor (MITF) [7]. This basic helix-loop-helix leucine zipper transcription factor MITF binds to E-box sequence in promoter region of genes coding for melanin synthesis, including tyrosinase (TYR), tyrosinase-related protein 1 (TRP1), and DOPA-chrome tautomerase (DCT)
The regulation of AChE has been proposed to be mediated by a cAMP/ protein kinase A (PKA)-dependent signaling [19, 26, 32]
Summary
Acetylcholinesterase (AChE) hydrolyzes the neurotransmitter acetylcholine in neurons. An AChE inhibitor greatly enhanced acetylcholine-mediated responses of melanogenic gene expression levels in vitro; this enhancement was not observed in the presence of agonists of the muscarinic acetylcholine receptor These results indicate that ACHE transcription is regulated by cAMP-dependent signaling during melanogenesis of B16F10 cells, and the effect of this enzyme on melanin production suggests that it has a potential role in skin pigmentation. The binding of ␣-MSH to melanocortin 1 receptor (MC1R) increases adenylyl cyclase activity, resulting in cAMP-induced transcription of the master transcriptional factor MITF [7] This basic helix-loop-helix leucine zipper transcription factor MITF binds to E-box sequence in promoter region of genes coding for melanin synthesis, including tyrosinase (TYR), tyrosinase-related protein 1 (TRP1), and DOPA-chrome tautomerase (DCT).
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