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Proteasome- and p38-dependent regulation of ERK3 expression

J Zimmermann1, N Lamerant, R Grossenbacher

  • 1Novartis Pharma AG, Oncology Research, WKL-125.13.14, CH-4002 Basel, Switzerland.

The Journal of Biological Chemistry
|January 20, 2001
PubMed

Insights

Proteasome inhibition increases extracellular signal-regulated kinase 3 (ERK3) expression, a response mediated by the p38 pathway. This ERK3 up-regulation may act as a cellular defense mechanism against proteasome inhibitor-induced stress.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Proteasome inhibition causes the accumulation of various proteins, including transcription factors and cyclins.
  • Gene transcription of specific proteins like p21(WAF1/CIP1) and ubiquitin increases upon proteasome inhibition.
  • Extracellular signal-regulated kinases (ERK) are key mediators in cell signaling pathways.

Purpose of the Study:

  • To investigate the effect of proteasome inhibitors on the expression of extracellular signal-regulated kinase 3 (ERK3).
  • To elucidate the signaling pathways involved in ERK3 up-regulation induced by proteasome inhibition.

Main Methods:

  • Treatment of cells with peptide-based proteasome inhibitors and lactacystin.
  • Analysis of ERK3 mRNA and protein expression levels.
  • Assessment of ERK3 up-regulation independence from p53, Bcl2, and caspase 3.
  • Inhibition of the p38 pathway using specific kinase inhibitors.
  • Ectopic expression of ERK3 in MCF-7 cells.

Main Results:

  • Proteasome inhibitors selectively up-regulate ERK3 mRNA and protein expression.
  • ERK3 up-regulation occurs independently of the p53, Bcl2, and caspase 3 cellular status.
  • p38 pathway kinase inhibitors block proteasome-dependent ERK3 induction.
  • Ectopic ERK3 expression confers increased resistance to proteasome inhibitors.

Conclusions:

  • ERK3 expression is induced by proteasome inhibition via p38 pathway activation.
  • ERK3 likely functions as an intracellular defense mechanism against proteasome inhibitor-induced cellular damage.
  • Targeting the p38 pathway or modulating ERK3 expression could influence cellular responses to proteasome inhibitors.

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