Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0278883 (metastatic melanoma)
 6,224 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Microtubule-associated protein 2 (MAP2), a neuron-specific protein, stabilizes microtubules and is critical for neurite outgrowth and dendrite development. Although MAP2 is widely used as a marker of neuronal differentiation, regulation of its transcription has not been investigated. We showed that MAP2 is frequently activated in human cutaneous melanoma. Here, we identified a 2.2 kb region that is sufficient for neuronal-specific expression in vitro and in vivo. Comparative analysis of the mouse, rat and human MAP2 promoter sequences showed the presence of a conserved bHLH factor binding sites. Electrophoretic mobility shift analysis, promoter mutagenesis and co-transfection experiments showed that NeuroD, a pro-neuronal differentiation factor, and Hairy and Enhancer of Split (HES1), a transcription repressor, are involved in the regulation of MAP2 promoter activity. Melanoma cells express both NeuroD and HES1. Chromatin immunoprecipitation showed that in metastatic melanoma cells N-box region of the MAP2 promoter is occupied by endogenous HES1. We show that the inhibition of Notch signaling, a regulator of HES1 gene expression, and/or shRNA knockdown of HES1 results in the upregulation of MAP2 promoter activity. Thus, our data suggest that Notch signaling, which is implicated in melanoma progression, and HES1 play a role in MAP2 gene regulation during melanoma progression.
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PMID:Transcriptional regulation of human MAP2 gene in melanoma: role of neuronal bHLH factors and Notch1 signaling. 1691 93

MAP2 is a neuron-specific microtubule-associated protein that binds and stabilizes dendritic microtubules. Previously, we showed that MAP2 expression is (a) activated in cutaneous primary melanoma and (b) inversely associated with melanoma tumor progression. We also showed that ectopic expression of MAP2 in metastatic melanoma cells inhibits cell growth by inducing mitotic spindle defects and apoptosis. However, molecular mechanisms of regulation of MAP2 gene expression in melanoma are not understood. Here, we show that in melanoma cells MAP2 expression is induced by the demethylating agent 5-aza-2'-cytidine, and MAP2 promoter is progressively methylated during melanoma progression, indicating that epigenetic mechanisms are involved in silencing of MAP2 in melanoma. In support of this, methylation of MAP2 promoter DNA in vitro inhibits its activity. Because MAP2 promoter activity levels in melanoma cell lines also correlated with activating mutation in BRAF, a gene that is highly expressed in neurons, we hypothesized that BRAF signaling is involved in MAP2 expression. We show that hyperactivation of BRAF-MEK signaling activates MAP2 expression in melanoma cells by two independent mechanisms, promoter demethylation or down-regulation of neuronal transcription repressor HES1. Our data suggest that BRAF oncogene levels can regulate melanoma neuronal differentiation and tumor progression.
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PMID:Oncogenic BRAFV600E induces expression of neuronal differentiation marker MAP2 in melanoma cells by promoter demethylation and down-regulation of transcription repressor HES1. 1988 May 19