Dual inhibitory roles of geldanamycin on the c-Jun NH2-terminal kinase 3 signal pathway through suppressing the expression of mixed-lineage kinase 3 and attenuating the activation of apoptosis signal-regulating kinase 1 via facilitating the activation of Akt in ischemic brain injury.
It is well documented that heat-shock protein (hsp90) plays an essential role in maintaining stability and activity of its clients. Recent studies have shown that geldanamycin (GA), an inhibitor of hsp90, could decrease the protein of mixed-lineage kinase (MLK) 3 and activate Akt; our previous research documented that MLK3 and Akt and subsequent c-Jun N-terminal kinase (JNK) were involved in neuronal cell death in ischemic brain injury. Here, we investigated whether GA could decrease the protein of MLK3 and activate Akt in rat four-vessel occlusion ischemic model. Our results showed that global cerebral ischemia followed by reperfusion could enhance the association of hsp90 with MLK3, the association of hsp90 with Src, and JNK3 activation. As a result, GA decreased the protein of MLK3 and down-regulated JNK activation. On the other hand, Src kinase was activated and phosphorylated Cbl, which then recruited the p85 subunit of phosphatidylinositol 3-kinase (PI-3K), resulting in PI-3K activation, and as a consequence increased Akt activation, which inhibited ASK1 activation and down-regulated JNK3 activation. In summary, our results indicated that GA showed a dual inhibitory role on JNK3 activation and exerted strong neuroprotection in vivo and in vitro, which provides a new possible approach for stroke therapy.
Wen
X-R
XR
Research Center for Biochemistry and Molecular Biology, Xuzhou Medical College, 84 West Huai-hai Road, Xuzhou 221002, Jiangsu, PR China.
Li
C
C
Zong
Y-Y
YY
Yu
C-Z
CZ
Xu
J
J
Han
D
D
Zhang
G-Y
GY
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D016227:Benzoquinones / Q000494:pharmacology*; D001930:Brain Injuries / Q000201:enzymology* / Q000209:etiology / Q000517:prevention & control; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005947:Glucose / Q000172:deficiency; D006624:Hippocampus / Q000166:cytology; D020244:Infarction, Middle Cerebral Artery / Q000150:complications; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism*; D008297:Male; D048057:Mitogen-Activated Protein Kinase 10 / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D010100:Oxygen / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors
D016227:Benzoquinones; D002867:Chromones; D004791:Enzyme Inhibitors; D047029:Lactams, Macrocyclic; D009025:Morpholines; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D048057:Mitogen-Activated Protein Kinase 10; D051058:Oncogene Protein v-akt; D048848:MAP Kinase Kinase Kinase 5; D005947:Glucose; D010100:Oxygen; C001277:geldanamycin