Parkin regulates Eg5 expression by Hsp70 ubiquitination-dependent inactivation of c-Jun NH2-terminal kinase.
Eg5 is a motor protein of the kinesin family that is critical for spindle assembly during mitosis and has recently been implicated in tumorigenesis. It is largely unknown how Eg5 expression is regulated in cells. In this study, we present the first evidence that the cellular Eg5 level is down-regulated by Parkin, an E3 ubiquitin ligase well known for its role in the development of Parkinson disease. Our data show that Parkin does not trigger Eg5 protein degradation through the ubiquitin-proteasome pathway. Instead, Parkin represses Eg5 gene transcription by blocking c-Jun binding to the activator protein 1 site present in the Eg5 promoter. Our data further show that Parkin inactivates c-Jun NH2-terminal kinase (JNK), resulting in decreased phosphorylation of c-Jun. The inactivation of JNK is further mediated by multiple monoubiquitination of Hsp70. Importantly, both the ubiquitination of Hsp70 and the subsequent inactivation of the JNK-c-Jun pathway are crucial for Parkin to down-regulate Eg5 expression. These results thus uncover a novel function for Parkin in modulating the expression of Eg5 through the Hsp70-JNK-c-Jun signaling pathway.
Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, Tianjin 300071, China.
Min
M
Liu
Ritu
R
Aneja
Xiaodong
X
Sun
Songbo
S
Xie
Hongxia
H
Wang
Xiaojing
X
Wu
Jin-Tang
JT
Dong
Minggang
M
Li
Harish C
HC
Joshi
Jun
J
Zhou
D002460:Cell Line; D005786:Gene Expression Regulation / Q000502:physiology*; D050884:HSP72 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016547:Kinesins / Q000096:biosynthesis*; D008938:Mitosis / Q000502:physiology; D010300:Parkinson Disease / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D008941:Spindle Apparatus / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination / Q000502:physiology*
D050884:HSP72 Heat-Shock Proteins; C470243:KIF11 protein, human; D016755:Proto-Oncogene Proteins c-jun; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D048031:JNK Mitogen-Activated Protein Kinases; D046988:Proteasome Endopeptidase Complex; D016547:Kinesins