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ERK1/2 can feedback-regulate cellular MEK1/2 levels. Cell Signal 2015 Oct;27(10):1939-48

Date

07/15/2015

Pubmed ID

26163823

Pubmed Central ID

PMC4540659

DOI

10.1016/j.cellsig.2015.07.003

Scopus ID

2-s2.0-84936994796   13 Citations

Abstract

Signal transduction of the Raf/MEK/ERK pathway is regulated by various feedback mechanisms. Given the greater molar ratio between Raf-MEK than between MEK-ERK in cells, it may be possible that MEK1/2 levels are regulated to modulate Raf/MEK/ERK activity upon pathway stimulation. Nevertheless, it has not been reported whether MEK1/2 expression can be subject to a feedback regulation. Here, we report that the Raf/MEK/ERK pathway can feedback-regulate cellular MEK1 and MEK2 levels. In different cell types, ΔRaf-1:ER- or B-Raf(V600E)-mediated MEK/ERK activation increased MEK1 but decreased MEK2 levels. These regulations were abrogated by ERK1/2 knockdown mediated by RNA interference, suggesting the presence of a feedback mechanism that regulates MEK1/2 levels. Subsequently, analyses using qPCR and luciferase reporters of the DNA promoter and 3' untranslated region revealed that the feedback MEK1 upregulation was in part attributed to increased transcription. However, the feedback MEK2 downregulation was only observed at protein levels, which was blocked by the proteasome inhibitors, MG132 and bortezomib, suggesting that the MEK2 regulation is mediated at a post-translational level. These results suggest that the Raf/MEK/ERK pathway can feedback-regulate cellular levels of MEK1 and MEK2, wherein MEK1 levels are upregulated at transcriptional level whereas MEK2 levels are downregulated at posttranslational level.

Author List

Hong SK, Wu PK, Karkhanis M, Park JI

Authors

Jong-In Park PhD Professor in the Biochemistry department at Medical College of Wisconsin
Pui Kei Wu PhD Instructor in the Biochemistry department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Cell Line, Tumor
Cyclin-Dependent Kinase Inhibitor p21
Feedback, Physiological
Gene Expression Regulation
Humans
MAP Kinase Kinase 1
MAP Kinase Kinase 2
MAP Kinase Signaling System
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
Proteasome Endopeptidase Complex
Proteolysis
Proto-Oncogene Proteins B-raf
Transcription, Genetic
Up-Regulation
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a