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MuRF1 Inhibits JNK Signaling in Cardiac Ischemia Reperfusion injury by Degrading Phosphorylated cJun
Author(s) -
Willis Monte S,
Li HuiHua,
Rodriguez Jessica E,
Li Luge,
Rojas Mauricio,
Lockyer Pamela,
Patterson Cam
Publication year - 2008
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.22.1_supplement.751.11
Subject(s) - phosphorylation , mg132 , kinase , ubiquitin , ubiquitin ligase , chemistry , microbiology and biotechnology , signal transduction , regulator , proteasome , biology , proteasome inhibitor , biochemistry , gene
We recently identified that increased expression of the cardiac Muscle Ring Finger‐1 (MuRF1) is cardio‐protective in ischemia reperfusion (I/R) injury in vivo. To begin to understand the underlying mechanism, we investigated how cardiac MuRF1 regulates JNK signaling, a key regulator of cell survival/death during I/R injury. Hearts from transgenic (Tg) mice over‐expressing cardiac MuRF1 underwent global I/R and were assayed for total and phosphorylated JNK and cJun. Compared to littermate wild type mice, MuRF1 Tg hearts had significant reductions in total and phospho‐cJun (but not JNK) after I/R injury. To determine how MuRF1 specifically interacts with phosphorylated cJun, H9C2 cardiomyocytes were transfected with MuRF1 and cJun expression plasmids and subjected to hypoxia/reoxygenation (H/R). MuRF1 immunoprecipitation pulled down phospho‐cJun specifically, and significant increases in cJun ubiquitination were identified. Phosphorylated cJun levels induced by H/R were blunted when MuRF1 was present, which was reversed by treatment with a proteasome inhibitor (MG132). These studies identify MuRF1 as the first E3 ligase that recognizes phosphorylated cJun, ubiquitinates it, and targets it for degradation by the proteasome. We hypothesize that cardiac MuRF1 over‐expression is cardio‐protective due in part to its ability to inhibit pro‐apoptotic signaling through the JNK pathway.