Abstract
Two brain disease-related genes, one coding for the protease inhibitor SERPINI1 which is down-regulated in brain tumors, and the other for the PDCD10 programmed cell death gene which is often mutated in cerebral cavernous malformation, are closely adjacent in a head-to-head configuration and separated by only 851 bp on human chromosome 3q26. The 851-bp intergenic region contains a GC-rich 175-bp minimal bidirectional promoter which is essential for transcriptional activation of the two flanking genes. The oncogenic c-Myc transcription factor was identified to bind to a non-canonical E-box element (5'-CATGCG-3') of the minimal bidirectional promoter to drive both gene expressions. Methylation at the specific C nucleotide within the E-box sequence (5'-CATG(m)CG-3'), however, would severely interfere with the binding of c-Myc to the E-box. These results suggest that c-Myc plays an important role in regulating the coordinated transcription of the PDCD10-SERPINI1 bidirectional gene pair, and is possibly involved in differential expressions of these two neighboring genes in central nervous system diseases such as brain cancer.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / metabolism*
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Azacitidine / analogs & derivatives
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Azacitidine / pharmacology
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Cell Line, Tumor
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Chromatin Immunoprecipitation / methods
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DNA Methylation / drug effects
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Decitabine
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Electrophoretic Mobility Shift Assay / methods
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Enzyme Inhibitors / pharmacology
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Glioblastoma
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Humans
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Molecular Sequence Data
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Mutagenesis, Site-Directed / methods
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Neuroblastoma
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Neuropeptides / genetics
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Neuropeptides / metabolism*
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Neuroserpin
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Promoter Regions, Genetic / genetics
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-myc / chemistry
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Proto-Oncogene Proteins c-myc / metabolism*
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Serpins / genetics
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Serpins / metabolism*
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Transcriptional Activation / drug effects
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Transcriptional Activation / physiology*
Substances
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Apoptosis Regulatory Proteins
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Enzyme Inhibitors
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MYC protein, human
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Membrane Proteins
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Neuropeptides
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PDCD10 protein, human
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-myc
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Serpins
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Decitabine
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Azacitidine