c-Myc regulates the coordinated transcription of brain disease-related PDCD10-SERPINI1 bidirectional gene pair

Mol Cell Neurosci. 2009 Sep;42(1):23-32. doi: 10.1016/j.mcn.2009.05.001. Epub 2009 May 13.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism*
  • Azacitidine / analogs & derivatives
  • Azacitidine / pharmacology
  • Cell Line, Tumor
  • Chromatin Immunoprecipitation / methods
  • DNA Methylation / drug effects
  • Decitabine
  • Electrophoretic Mobility Shift Assay / methods
  • Enzyme Inhibitors / pharmacology
  • Glioblastoma
  • Humans
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed / methods
  • Neuroblastoma
  • Neuropeptides / genetics
  • Neuropeptides / metabolism*
  • Neuroserpin
  • Promoter Regions, Genetic / genetics
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-myc / chemistry
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Serpins / genetics
  • Serpins / metabolism*
  • Transcriptional Activation / drug effects
  • Transcriptional Activation / physiology*

Substances

  • Apoptosis Regulatory Proteins
  • Enzyme Inhibitors
  • MYC protein, human
  • Membrane Proteins
  • Neuropeptides
  • PDCD10 protein, human
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-myc
  • Serpins
  • Decitabine
  • Azacitidine