1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine has a transient proliferative effect on PC12h cells and nerve growth factor additively promotes this effect: possible involvement of distinct mechanisms of activation of MAP kinase family proteins.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a potent inducer of cell death, producing reactive oxygen species (ROS) and causing apoptosis in PC12h cells at 1 mM [Shimoke et al., J. Neurosci. Res. 63 (2001) 402-409]. We showed here that MPTP also had a weak proliferative effect on PC12h at 500 microM when treated for 24 h. The proliferative effect was additive within 24 h cells when nerve growth factor (NGF) was present in the culture medium, but NGF promoted cell differentiation 2 or 3 days after. Use of PD98059, a specific inhibitor of MEK1 located upstream of extracellular signal-regulated kinases (ERKs), revealed that the NGF- and MPTP-induced proliferative effect depends on the MEK1 pathway because PD98059 diminished the proliferation completely, and interestingly, NGF and MPTP promoted sustained activation of ERKs. Moreover, we observed that MPTP increased the activity of p38 MAPK but not c-jun N-terminal kinase (JNK) in 30 min. We also observed that SB203580, a specific inhibitor of p38 MAPK, decreased cell viability. These results suggest that NGF and MPTP cooperate to promote acute cell proliferation via the sustained ERKs and the p38 MAPK pathway within 24 h in PC12h cells.
Shimoke
Koji
K
Second Department of Pathology, Tokyo Medical University, 6-7-1 Nishi-Shinjuku, Shinjuku-ku, Tokyo 160-0023, Japan. shimoke@rio.odn.ne.jp
Kudo
Motoshige
M
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology*; D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000201:enzymology* / Q000503:physiopathology; D002455:Cell Division / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000187:drug effects / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism; D020932:Nerve Growth Factor / Q000378:metabolism* / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology*; D016716:PC12 Cells; D020734:Parkinsonian Disorders / Q000201:enzymology* / Q000503:physiopathology; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D017382:Reactive Oxygen Species; D020932:Nerve Growth Factor; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D017346:Protein Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases; D000111:Acetylcysteine