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Statin mediated transactivation of the ERK5 mitogen activated protein kinase
Author(s) -
Chu Uyen Bao,
Yang Jay
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.657.2
Subject(s) - transactivation , statin , geranylgeranyl pyrophosphate , prenylation , cancer research , chemistry , pharmacology , microbiology and biotechnology , biology , transcription factor , biochemistry , gene , enzyme
Statins are potent inhibitors of cholesterol biosynthesis and are clinically beneficial in preventing coronary heart disease. Independent of their lipid‐lowering effects, these compounds have been shown to improve endothelial function and inhibit the thrombogenic response. Here, we show that the MAP kinase ERK5 that functions both as a kinase and as a transcriptional co‐activator is transactivated by statins. We used a Gal4 DNA binding domain‐ERK5 fusion co‐expressed with a Gal4‐luciferase reporter to examine the mechanism of the statin‐mediated transactivation of ERK5. At 10 μM, cerivastatin, fluvastatin, pitavastatin, and simvastatin exhibited ERK5 transactivation. Western blots revealed that the statin‐mediated ERK5 transactivation is through phosphorylation of the TEY motif. Supplementing the statin‐treated cells with geranylgeranyl pyrophosphate abrogated transactivation suggesting that transactivation involves inhibition of protein prenylation by geranylgeranyl transferase I which prenylates the Rho/Rac/CDC42 family of GTPases. Microarray analyses are underway to examine the downstream targets of statin‐mediated ERK5 transactivation via the Rho/Rac/CDC42 ERK5 axis. These data will aid in the future design of therapeutics mimicking the beneficial effects of ERK5 activation such as endothelial cell protection and enhanced recovery from myocardial ischemia.