6-Hydroxydopamine-induced PC12 cell death is mediated by MEF2D down-regulation.
Recently, it was reported that in a 4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model, neuronal cell death is associated with the cdk5-mediated hyperphosphorylation of myocyte enhancer factor 2 (MEF2), a transcription factor that is critically required for neuronal survival. In the present study, we investigated the possible involvement of cdk5-mediated MEF2D down-regulation on 6-hydroxydopamine (6-OHDA)-induced PC12 cell death. 6-OHDA was found to significantly increase nitric oxide (NO) production and to induce apoptosis in a time-dependent manner in PC12 cells. Furthermore, 6-OHDA was found to markedly reduce MEF2D levels under conditions that could induce PC12 cell apoptosis. In addition, PC12 cell death and MEF2D degradation by 6-OHDA were prevented by the cdk5 inhibitor roscovitine, but roscovitine could not restore the 6-OHDA-induced inactivation of Akt. These results suggest that the cell death and MEF2D degradation caused by 6-OHDA are dependent on cdk5 activity. On the other hand, roscovitine enhanced the 6-OHDA-induced activations of ERK1/2 and JNK, but reduced the 6-OHDA-induced activation of p38. These results suggest that PC12 cell death by 6-OHDA appears to be regulated by the down-regulation of MEF2D via some interaction between cdk5 and MAP kinase.
Department of Pharmacology, School of Medicine, Institute of Medical Sciences, Jeju National University, Jeju, South Korea.
Min-Kyoung
MK
Kim
Sang-Cheol
SC
Kim
Jung-Il
JI
Kang
Jae-Hee
JH
Hyun
Hye-Jin
HJ
Boo
Su-Yong
SY
Eun
Deok-Bae
DB
Park
Eun-Sook
ES
Yoo
Hee-Kyoung
HK
Kang
Ji-Hoon
JH
Kang
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics / Q000378:metabolism; D053938:DNA Fragmentation; D015536:Down-Regulation; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D064326:MEF2 Transcription Factors; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D018006:Myogenic Regulatory Factors / Q000235:genetics / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D016627:Oxidopamine / Q000494:pharmacology*; D016716:PC12 Cells / Q000187:drug effects* / Q000502:physiology*; D047428:Protein Kinase Inhibitors / Q000378:metabolism; D011687:Purines / Q000378:metabolism; D051381:Rats; D000077546:Roscovitine; D015398:Signal Transduction / Q000502:physiology
D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors; D047428:Protein Kinase Inhibitors; D011687:Purines; D000077546:Roscovitine; D009569:Nitric Oxide; D016627:Oxidopamine; D051360:Cyclin-Dependent Kinase 5; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases