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Transcriptional regulation of early growth response genes in FOS-expressing PC-12 cells

E Ito1, N Nomura, R Narayanan

  • 1Department of Molecular Genetics, Roche Research Center, Nutley, New Jersey 07110.

Cell Regulation
|March 1, 1990
PubMed

Insights

Deregulated c-fos expression in PC-12 cells inhibits nerve growth factor (NGF)-induced gene activation and differentiation. This effect occurs at the c-fos promoter level, impacting early response gene expression.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Neuroscience

Background:

  • Nerve growth factor (NGF) typically induces differentiation in PC-12 cells via c-fos and c-jun activation.
  • Aberrant c-fos expression can disrupt normal cellular responses to growth factors and signaling molecules.

Purpose of the Study:

  • To investigate the impact of deregulated c-fos expression on NGF-induced gene activation and PC-12 cell differentiation.
  • To determine how FOS-expressing PC-12 cells respond to various signaling agents, including growth factors and second messengers.

Main Methods:

  • Generation of stable FOS-expressing PC-12 cell lines (PC-12 fos).
  • Treatment of PC-12 and PC-12 fos cells with NGF, EGF, bFGF, IL-1 beta, IL-6, db cAMP, and Ca-ionophore.
  • Analysis of early response gene expression (egr-1, c-fos, c-jun, jun-B, jun-D) using quantitative methods.
  • Assessment of gene regulation at the promoter level using a fos promoter-chloramphenicol acetyltransferase (promoter-CAT) reporter assay.

Main Results:

  • Deregulated c-fos expression in PC-12 cells significantly downregulated NGF-, bFGF-, db cAMP-, and Ca-ionophore-induced c-fos and c-jun activation.
  • EGF-induced activation of these early response genes remained unaffected in FOS-expressing PC-12 cells.
  • Activation of egr-1 by Ca-ionophore and db cAMP was completely inhibited in PC-12 fos cells.
  • jun-D exhibited high basal levels and was the least regulated gene across all treatments and cell types.

Conclusions:

  • Constitutive c-fos expression disrupts signaling pathways essential for NGF-induced differentiation in PC-12 cells.
  • The observed downregulation of gene activation occurs at the c-fos promoter level, indicating a feedback mechanism.
  • PC-12 cells with deregulated c-fos display differential responses to various stimuli, highlighting pathway specificity.

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