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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.
Abstract:
Proteasome inhibition leads to accumulation of transcription factors, heat shock proteins, cyclins, and other proteasome substrate proteins by blocking their proteolytic degradation. An increase in gene transcription upon proteasome inhibition was found for a group of proteins, including p21(WAF1/CIP1), ubiquitin, and transcription factors. In this study, we have demonstrated selective up-regulation of extracellular signal-regulated kinase 3 (ERK3) mRNA and protein expression upon treatment with peptide-based proteasome inhibitors or lactacystin. ERK3 is a family member of the mitogen-activated protein kinases (also called ERK) that are key mediators of signal transduction from the cell surface to the nucleus. ERK3 up-regulation is independent of the p53, Bcl2, and caspase 3 status of cells. p38 pathway kinase inhibitors prevent proteasome-dependent ERK3 induction and enhance the antiproliferative effect of proteasome inhibitors. MCF-7 cells expressing ERK3 ectopically show increased resistance toward proteasome inhibition. The results indicate that ERK3 expression is a consequence of p38 pathway activation and most probably represents an intracellular defense or rescue mechanism against cell stress and damage induced by proteasome inhibition.
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.