Eisen, Timothy; (1996) Regulation of cell type-specific gene expression in melanocytes and melanoma. Doctoral thesis (Ph.D.), University College London (United Kingdom).

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Abstract

Recent advances have demonstrated that the precise regulation of transcription, essential for normal cell behaviour, is achieved by a complex network of transcription factors. In contrast to the detailed knowledge of general regulatory mechanisms, little is known of the factors responsible for determining cell type-specific gene expression. Melanocytes and their malignant counterpart, melanoma, are vivid examples of this. Together with the retinal pigment epithelium, melanocytes are the sole producers of the pigment melanin in a pathway whose rate-limiting step is catalysed by the pigment cell-specific enzyme tyrosinase. Powerful evidence links development of the malignant phenotype to loss of control of cell type-specific gene expression, reflected in the tendency of melanomas both to underexpress tyrosinase and aberrantly to express the DR class II major histocompatability complex marker. An understanding of melanocyte transcriptional regulation will provide an insight into the control of cell type-specific gene expression and its malfunction in the malignant process. The results presented here show that melanocyte-specific expression of the tyrosinase gene is maintained by a number of mechanisms: The microphthalmia gene product (mi) transcription factor is expressed in melanocytes where it binds to consensus elements at the tyrosinase initiator and 100 bases upstream of it and activates the promoter. Its cardinal role at the initiator is antagonised by a POU-domain transcription factor, identified here as Brn-2, which binds, in vitro, in a mutually exclusive manner at an overlapping site. Unlike in melanocytes, Brn-2 is expressed at high levels in melanoma where it can repress the tyrosinase promoter and activate the MHC DR promoter. Brn-2 is itself regulated by phosphorylation by cAMP-dependent kinase which both prevents DNA binding and relocates Brn-2 from nucleus to cytoplasm. The significance of these results in melanocyte development and transformation is discussed.

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