Midkine inhibits apoptosis via extracellular signal regulated kinase (ERK) activation in PC12 cells.
Midkine (MK) is a new member of the family of heparin-binding neurotrophic factors. MK has several important biological effects and plays an important role in the development and survival of neurons. The mechanism by which MK exerts its neurotrophic actions, however has not been sufficiently clarified. To understand the intracellular pathway activated by MK, we established an apoptosis-induction system with the neuronal cell line PC12 and studied the involvement of the mitogen-activated protein kinase (MAPK) cascade in neuroprotective actions of MK. We demonstrate here that MK rescued PC12 cells from apoptosis induced by serum deprivation in a dose-dependent manner. MK also activated extracellular signal-regulated kinases 1 and 2 (ERK1 and ERK2), which are well known as signal transducer acting downstream several receptors. PD98059, an inhibitor of MAPK kinase (MAPKK), inhibited ERK activation and also prevented the trophic effect of MK. These results indicate that MK exerts its neuroprotective actions mainly via ERK activation.
Owada
K
K
Department of Neurology, Faculty of Medicine, Tokyo Medical and Dental Unviersity, Japan.
Sanjyo
N
N
Kobayashi
T
T
Kamata
T
T
Mizusawa
H
H
Muramatsu
H
H
Muramatsu
T
T
Michikawa
M
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002352:Carrier Proteins / Q000494:pharmacology* / Q000502:physiology*; D004396:Coloring Agents; D016895:Culture Media, Serum-Free; D016207:Cytokines; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D020287:In Situ Nick-End Labeling; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D000078792:Midkine; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D009414:Nerve Growth Factors / Q000494:pharmacology / Q000502:physiology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016716:PC12 Cells; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology; D013778:Tetrazolium Salts; D013844:Thiazoles
D002352:Carrier Proteins; D004396:Coloring Agents; D016895:Culture Media, Serum-Free; D016207:Cytokines; D004791:Enzyme Inhibitors; D005419:Flavonoids; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D011994:Recombinant Proteins; D013778:Tetrazolium Salts; D013844:Thiazoles; D000078792:Midkine; D020928:Mitogen-Activated Protein Kinases; C022616:thiazolyl blue; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one