Molecular mechanisms of pigment cell differentiation.

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Microphthalmia-associated transcription factor (MITF) plays an important role in pigment cell differentiation. Transient transfection assays have shown that MITF transactivates the tyrosinase and tyrosinase-related protein 1 (TRP-1) gene promoters, but not the TRP-2 gene promoter. Unexpectedly, a truncated MITF lacking the carboxyl-terminal 125 amino acids could transactivate the TRP-2 promoter. Consequently, using a yeast two-hybrid system, we have cloned several cDNAs coding for proteins which may interact with MITF's carboxyl-terminal portion. Moreover, we have identified three novel MITF isoforms, termed A,B,and H types, which differ in their amino-termini and expression patterns. An authentic MITF has been renamed MITF-M,because it is exclusively expressed in melanocytes and melanoma. These four isoforms share the entire carboxyl-terminal portion, including a basic helix-loop-helix and leucine zipper structure. We have shown that MITF-A,like MITF-M,transactivates the tyrosinase and TRP-1 gene promoters, but not-TRP-2. MITF-A mRNA is predominantly expressed in retinal pigment epithelium. In addition, we have obtained the following results as summarized below. 1.The threc cis-regulatory elements of the human tyrosinase gene have been identified, and each of these elements contains one copy of a CATGTG motif and is required for pigment cell-specific transcription. 2.A human TFEC isoform, termed TFECL,has been identified as a transcriptional activator. TFECL contains an activation domain which is deleted in rat TFEC,originally identified as a transcriptional repressor in rat chondrosarcoma. 3.The amino acid sequence of rat neurofibromin has been deduced from the nucleotide sequence of its cDNA.4.Adrenomedullin, a potent vasodilator peptide, has been shown to be produced and secreted by cultured choroid plexus carcinoma cells, a rare neoplasm derived from the epithelium of the choroid plexus.