Phosphorylation and Inactivation of Myeloid Cell Leukemia 1 by JNK in Response to Oxidative Stress*
- Seiji Inoshita‡,§,
- Kohsuke Takeda‡,
- Takiko Hatai‡,
- Yoshio Terada§,
- Makoto Sano¶,
- Junichi Hata¶,
- Akihiro Umezawa¶ and
- Hidenori Ichijo‡‖
- From the ‡Laboratory of Cell Signaling, Department of Hard Tissue Engineering, Division of Bio-Matrix, §Homeostasis Medicine and Nephrology, Department of Regulation of Internal Environment and Reproduction, Division of Systemic Organ Regulation, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8549, Japan, and the ¶Department of Pathology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
Abstract
Oxidative stress induces JNK activation, which leads to apoptosis through mitochondria-dependent caspase activation. However, little is known about the mechanism by which JNK alters mitochondrial function. In this study, we investigated the role of phosphorylation of myeloid cell leukemia 1 (Mcl-1), an anti-apoptotic member of the Bcl-2 family, in oxidative stress-induced apoptosis. We found that JNK phosphorylated Ser-121 and Thr-163 of Mcl-1 in response to stimulation with H2O2 and that transfection of unphosphorylatable Mcl-1 resulted in an enhanced anti-apoptotic activity in response to stimulation with H2O2. JNK-dependent phosphorylation and thus inactivation of Mcl-1 may be one of the mechanisms through which oxidative stress induces cellular damage.
- JNK
- c-Jun NH2-terminal kinase
- ASK
- apoptosis signal-regulating kinase
- MAPK
- mitogen-activated protein kinase
- MAPKKK
- MAPK kinase kinase
- Mcl-1
- myeloid cell leukemia 1
- PAE
- porcine aortic endothelial
- ERK
- extracellular signal-regulated kinase
- HA
- hemagglutinin
- DTT
- dithiothreitol
- GST
- glutathioneS-transferase
- WT
- wild type
- Received August 5, 2002.
- Revision received September 4, 2002.
- The American Society for Biochemistry and Molecular Biology, Inc.
