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EGR1, EGR2, and EGR3 activate the expression of their coregulator NAB2 establishing a negative feedback loop in cells

Joerg Kumbrink1, Kathrin H Kirsch, Judith P Johnson

  • 1Institute for Immunology, University of Munich, Munich 80336, Germany.

Journal of Cellular Biochemistry
|May 28, 2010
PubMed

Insights

Early growth response (EGR) transcription factors EGR2 and EGR3 activate NAB2 expression in melanoma and carcinoma cells, establishing a negative feedback loop. Their interplay with EGR1 highlights context-dependent regulation of gene expression.

Area of Science:

  • Molecular Biology
  • Gene Regulation
  • Cancer Biology

Background:

  • Early growth response (EGR) transcription factors (EGR1, EGR2, EGR3) regulate key cellular processes.
  • NAB2 acts as a modulator for EGR factors, with differential expression patterns observed in various cell types.
  • Previous studies show EGR1 activates NAB2 in cancer cells, while EGR2/EGR3 inhibit it in T lymphocytes.

Purpose of the Study:

  • To investigate the role of EGR2 and EGR3 in regulating NAB2 expression within melanoma and carcinoma cells.
  • To elucidate the cooperative and individual effects of EGR1, EGR2, and EGR3 on NAB2 transcription.
  • To understand the feedback mechanisms between EGR factors and NAB2.

Main Methods:

  • Analysis of NAB2 promoter activity in response to EGR factor induction.
  • Use of small interfering RNAs (siRNAs) to deplete EGR2 and EGR3 expression.
  • Kinetic studies to assess the temporal dynamics of EGR and NAB2 expression.
  • Investigation of cis-regulatory elements involved in EGR-mediated NAB2 activation.

Main Results:

  • EGR2 and EGR3, similar to EGR1, induce NAB2 expression in melanoma and carcinoma cells.
  • EGR1 and EGR3 exhibit synergistic effects on the NAB2 promoter, showing greater potency than EGR2.
  • NAB2 represses the activation of its own promoter by EGR factors, indicating a negative feedback loop.
  • EGR2 and EGR3 are crucial for sustained NAB2 expression, while EGR1 contributes to initial induction.
  • Depletion of EGR3 also reduced EGR2 levels, identifying EGR2 as a target gene of EGR3.

Conclusions:

  • EGR1, EGR2, and EGR3 activate NAB2 transcription in cells of neuroectodermal and epithelial origin.
  • A negative feedback loop exists where NAB2 represses EGR-mediated transcription of its own gene.
  • The relationship between EGR factors and NAB2 expression is complex and cell-context dependent.

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