The p38(MAPK) signaling pathway regulates neuronal apoptosis through the phosphorylation of the retinoblastoma protein.
We investigated the role of SB202190, a selective p38 mitogen-activated protein kinase (MAPK) inhibitor in cerebellar granule neurons (CGC) in response to serum potassium deprivation (S/K deprivation), an apoptotic stimulus. CGC apoptosis after S/K deprivation was shown to be mediated through cell cycle re-entry and the induction of transcription factor E2F-1. We found that SB 202190 (10muM) inhibits retinoblastoma protein (pRb) phosphorylation, in response to S/K deprivation. Moreover, the expression of cyclin E and E2F-1 were also significantly decreased. Interestingly, SB202190 did not affect or modulate the increase in the protein expression levels of cyclin D1. Similarly, p-Akt and p-GSK3 protein levels, measured after 12h S/K deprivation, did not appear to be regulated by SB 202190 (10muM). These data indicate that the neuroprotective effects of the p38 inhibitor were not mediated via Akt activation. In conclusion, these results suggest that p38MAPK converged with the cell cycle in S/K deprivation-induced apoptosis through pRb phosphorylation.
Yeste-Velasco
Marc
M
Unitat de Farmacologia i Farmacognòsia, Facultat de Farmàcia, Institut de Biomedicina (IBUB), Centros de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Universitat de Barcelona, Avinguda Diagonal 643, 08028 Barcelona, Spain.
Folch
Jaume
J
Pallàs
Mercè
M
Camins
Antoni
A
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002452:Cell Count; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D002467:Cell Nucleus / Q000648:ultrastructure; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D053938:DNA Fragmentation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005434:Flow Cytometry; D007093:Imidazoles / Q000494:pharmacology*; D009363:Neoplasm Proteins / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019572:Retinal Neoplasms / Q000378:metabolism*; D012175:Retinoblastoma / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology*
D004791:Enzyme Inhibitors; D007093:Imidazoles; D009363:Neoplasm Proteins; D011725:Pyridines; D048051:p38 Mitogen-Activated Protein Kinases; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole