"In melanocytes and in melanoma cells, cyclic AMP (cAMP)-elevating agents stimulate melanogenesis and increase the transcription of tyrosinase, the rate-limiting enzyme in melanin synthesis. However, two other enzymes, tyrosinase-related protein 1 (TRP1) and TRP2, are required for a normal melanization process leading to eumelanin synthesis. In B16 melanoma cells, we demonstrated that stimulation of melanogenesis by cAMP-elevating agents results in an increase in tyrosinase, TRP1, and TRP2 expression. cAMP, through a cAMP-dependent protein kinase pathway, stimulates TRP1 and TRP2 promoter activities in both B16 mouse melanoma cells and normal human melanocytes. Regulation of the TRP1 and TRP2 promoters by cAMP involves a M box and an E box."
"[M]icrophthalmia, a basic helix-loop-helix transcription factor, strongly stimulates the transcriptional activities of the TRP1 and TRP2 promoters, mainly through binding to the M boxes."
"In mammals, pigmentation results from the synthesis and distribution of melanin in the skin, hair bulbs, and eyes. Melanin synthesis (melanogenesis) takes place in the melanocyte after differentiation of the nonpigmented precursor, the melanoblast (27). Three melanocyte-specific enzymes, tyrosinase, tyrosinase-related protein 1 (TRP1), and TRP2, are involved in this enzymatic process that converts tyrosine to melanin pigments. Although these proteins have similar structures and features, they are expressed by different genes and possess distinct enzymatic activities. Tyrosinase, encoded by the albino locus of the mouse, catalyzes the conversion of tyrosine to 3,4-dihydroxyphenylalanine (DOPA) and of DOPA to DOPA quinone (14, 25, 31). TRP2, encoded by the mouse slaty locus, possesses a Dopachrome tautomerase activity, converting the Dopachrome to 5,6-dihydroxyindole-2-carboxylic acid (DHICA) (3, 19, 42). TRP1, which has been mapped in mouse to the brown locus, catalyzes the oxidation of DHICA to indole-5,6-quinone-2-carboxylic acid (21, 24)."
"In the TRP1 promoter, the M box (GTCATGTGCT) [is] located between bp −44 and −33 upstream from the initiation start site [...] and the E box (CAAGTG) [is] located between bp −238 and −233 [...] In the TRP2 promoter, the M box (GTCATGTGCT) [is] located between bp −135 and −129 upstream from the initiation start site [...] the E box (CACATG) [is] between bp −346 and −340 [and] the cAMP response element (CRE; TGAGGTCA) [is] located between bp −239 and −232 [...]."
The "regulation of TRP1 gene expression by PKA in B16 melanoma cells involves the M box just upstream of the TATA box."
"Tyrosinase and TRP1 promoters share an 11-bp motif (AGTCATGTGCT) termed the M box located upstream of the TATA box. This motif binds microphthalmia, a basic helix-loop-helix transcription factor that increases tyrosinase and TRP1 promoter activities, thereby playing a key role in the tissue-specific expression of these genes (11, 29, 40). In the TRP2 promoter, a homologous sequence (GTCATGTGCT) is also found upstream of the TATA box (41)."
- Corine Bertolotto, Roser Buscà, Patricia Abbe, Karine Bille, Edith Aberdam, Jean-Paul Ortonne, and Robert Ballotti (February 1998). "Different cis-Acting Elements Are Involved in the Regulation of TRP1 and TRP2 Promoter Activities by Cyclic AMP: Pivotal Role of M Boxes (GTCATGTGCT) and of Microphthalmia". Molecular and Cellular Biology 18 (2): 694–702. PMID 9447965. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC108780/. Retrieved 8 December 2018.