Published online 11 August 2006
Nucleic Acids Research, 2006, Vol. 34, No. 13 3819-3832
© 2006 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commerical use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Transcriptional regulation of human MAP2 gene in melanoma: role of neuronal bHLH factors and Notch1 signaling
Department of Dermatology, University of Wisconsin 1300 University Avenue, B25, Madison, WI 53706, USA 1 Department of Dairy and Animal Sciences, Pennsylvania State University, University Park PA, USA
*To whom correspondence should be addressed. Tel: +1 608 263 5362; Fax: +1 608 263 5223; Email: setaluri{at}wisc.edu
Received May 6, 2006. Revised June 16, 2006. Accepted June 20, 2006.
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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