Impaired apoptosis in lymphoblasts from Alzheimer's disease patients: cross-talk of Ca2+/calmodulin and ERK1/2 signaling pathways.
We have analyzed the intracellular signals that allow lymphoblasts from Alzheimer's disease (AD) patients to escape from serum deprivation-induced apoptosis. The following observations suggested that modulation of ERK1/2 activity by Ca(2+)/calmodulin (CaM) is involved in preventing apoptosis: (i) ERK1/2 activity seems to support lethality in control cells, as PD98059, the inhibitor of the activating MEK prevented cell death; (ii) control cells show a persistent and higher stimulation of ERK1/2 than that of AD cells in the absence of serum; (iii) CaM antagonists have no effects on control cells, but sensitize AD cells to death induced by serum withdrawal and increased ERK1/2 phosphorylation, and (iv) no apoptotic effects of CaM antagonists were observed in AD cells treated with PD98059. These results suggest the existence of an activation threshold of the ERK1/2 pathway setting by Ca(2+)/CaM-dependent mechanisms, which appears to be the critical factor controlling cell survival or death decision under trophic factor withdrawal.
Bartolomé
F
F
Department of Cellular and Molecular Pathophysiology, Centro de Investigaciones Biológicas, Ramiro de Maéztu 9, Madrid, Spain.
de Las Cuevas
N
N
Muñoz
U
U
Bermejo
F
F
Martín-Requero
A
A
D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001402:B-Lymphocytes / Q000502:physiology; D002118:Calcium / Q000378:metabolism*; D002147:Calmodulin / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival; D016895:Culture Media, Serum-Free; D004789:Enzyme Activation; D006801:Humans; D008214:Lymphocytes / Q000166:cytology / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
D002147:Calmodulin; D016895:Culture Media, Serum-Free; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D002118:Calcium