A tissue-restricted cAMP transcriptional response: SOX10 modulates alpha-melanocyte-stimulating hormone-triggered expression of microphthalmia-associated transcription factor in melanocytes.

Abstract	alpha-Melanocyte-stimulating hormone (MSH) utilizes cAMP to trigger pigmentation of melanocytes via activation of melanocyte-restricted microphthalmia-associated transcription factor (M-MITF) expression. M-MITF is a melanocyte-restricted helix-loop-helix transcription factor capable of transactivating promoters for multiple genes whose products modulate pigmentation. Although M-MITF promoter activation by MSH is known to occur through a conserved cAMP-response element (CRE), it remains unclear how this CRE exhibits such exquisitely tissue-restricted responsiveness. Here we show that cAMP-mediated CRE-binding protein activation of the M-MITF promoter requires a second DNA element located approximately 100 bp upstream, a site that is bound and activated by SOX10. Mutations in the SOX10 transcription factor, like MITF, results in a disorder known as Waardenburg Syndrome. The cAMP response of the M-MITF promoter was analyzed in melanoma and neuroblastoma cells (which are neural crest-derived but lack both M-MITF and SOX10 expression). M-MITF promoter responsiveness to cAMP was found to depend upon SOX10, and reciprocally, SOX10 transactivation was dependent upon the CRE. Ectopic SOX10 expression, in cooperation with cAMP signaling, activated the M-MITF promoter function and the expression of measurable endogenous M-MITF transcripts in neuroblastoma cells. SOX10dom, a mutant allele, failed to cooperate with cAMP in neuroblastoma cells and attenuated the cAMP responsiveness of the M-MITF promoter in melanoma cells. These observations demonstrate a means whereby the ubiquitous cAMP signaling machinery is harnessed to produce a highly tissue-restricted transcriptional response by cooperating with architectural factors, in this case SOX10.
Authors	Wade E Huber, E Roydon Price, Hans R Widlund, Jinyan Du, Ian J Davis, Michael Wegner, David E Fisher
Journal	The Journal of biological chemistry (J Biol Chem) Vol. 278 Issue 46 Pg. 45224-30 (Nov 14 2003) ISSN: 0021-9258 [Print] United States
PMID	12944398 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
Chemical References	DNA-Binding Proteins High Mobility Group Proteins MITF protein, human Microphthalmia-Associated Transcription Factor SOX10 protein, human SOXE Transcription Factors Transcription Factors alpha-MSH Cyclic AMP Luciferases
Topics	Alleles Blotting, Western Cell Line, Tumor Cells, Cultured Cyclic AMP (metabolism) DNA-Binding Proteins (metabolism) Genes, Reporter Genetic Vectors High Mobility Group Proteins (metabolism) Humans Luciferases (metabolism) Melanocytes (metabolism) Microphthalmia-Associated Transcription Factor Models, Genetic Mutation Neuroblastoma (metabolism) Phosphorylation Promoter Regions, Genetic Protein Binding Protein Structure, Tertiary Reverse Transcriptase Polymerase Chain Reaction SOXE Transcription Factors Transcription Factors (metabolism) Transcription, Genetic Transcriptional Activation Transfection alpha-MSH (metabolism)

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