ERK1/2 can feedback-regulate cellular MEK1/2 levels. Cell Signal 2015 Oct;27(10):1939-48
Date
07/15/2015Pubmed ID
26163823Pubmed Central ID
PMC4540659DOI
10.1016/j.cellsig.2015.07.003Scopus ID
2-s2.0-84936994796 (requires institutional sign-in at Scopus site) 21 CitationsAbstract
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 JIAuthor
Jong-In Park PhD Professor in the Biochemistry department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Cell Line, TumorCyclin-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
