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A novel MASH1 enhancer with N-myc and CREB-binding sites is active in neuroblastoma.

Journal article
Authors Fujiko Watt
Rie Watanabe
Weiwen Yang
N Ågren
Yvonne Arvidsson
Keiko Funa
Published in Cancer gene therapy
Volume 14
Issue 3
Pages 287-96
ISSN 0929-1903
Publication year 2007
Published at Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology
Pages 287-96
Language en
Links dx.doi.org/10.1038/sj.cgt.7701012
Keywords Animals, Basic Helix-Loop-Helix Transcription Factors, genetics, metabolism, Binding Sites, Chromatin Immunoprecipitation, Cyclic AMP Response Element-Binding Protein, metabolism, Electrophoretic Mobility Shift Assay, Enhancer Elements (Genetics), Gene Expression Regulation, Neoplastic, Humans, Mice, Neuroblastoma, genetics, metabolism, pathology, Promoter Regions (Genetics), Proto-Oncogene Proteins c-myc, genetics, metabolism, Regulatory Sequences, Nucleic Acid, Tumor Cells, Cultured
Subject categories Medical and Health Sciences

Abstract

Neuroblastoma is one of the most common solid tumors in childhood. With the aim of developing a targeting vector for neuroblastoma, we cloned and characterized an enhancer in the 5'-flanking regions of the MASH1 gene by a random-trap method from a 36 kb cosmid DNA. The enhancer-containing clone was identified by the expression of GFP when transfected into neuroblastoma cell lines. The enhancer-luciferase activity is higher in neuroblastoma cell lines, IMR32, BE2 and SH-SY5Y, compared with those in non-neuroblastoma cell lines, U1242 glioma, N417 small cell lung cancer and EOMA hemangioma. The core enhancer was determined within a 0.2 kb fragment, yielding three- to fourfold higher activity than that of the MASH1 promoter alone in IMR32 and BE2. This area possesses GATA- and CREB-binding sites, as well as the E-box. EMSA on this area demonstrated that CREB/ATF could bind the DNA. Chromatin immunoprecipitation assay revealed that N-myc, CREB, and co-activators CBP and PCAF, but not HDAC1, are bound to the core enhancer at the same time as the co-activators and N-myc bind to the promoter. This supports the idea that the commonly overexpressed genes HASH1 and N-myc are regulated in concert, confirming their importance as prognostic markers or targets for therapy.

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