Altered transcriptional regulators in response to serum in immortalized lymphocytes from Alzheimer's disease patients.
Cell cycle disturbances may precede neuronal death in Alzheimer's disease (AD). We described alterations, in lymphocytes from AD patients, on the activity of two transcription factors, E2F and NF-kappaB, involved in cell proliferation and survival regulation, demonstrating that cell cycle dysfunction also occurs in peripheral cells. The analysis of E2F-DNA binding activity revealed lower signal intensity of protein-DNA complexes in AD cells, which correlated with increased phosphorylation of retinoblastoma (pRb) related proteins and enhanced proliferation. The calmodulin (CaM) antagonist calmidazolium (CMZ) abrogated the increased activity of AD cells by partially dephosphorylating pRb and p130. The NF-kappaB-DNA binding activity increased as cell progress through the cell cycle. The reduced NF-kappaB activation observed in AD cells appears not to be related to the increased phosphorylation of the pRb family proteins nor with the enhanced proliferative activity of AD cells, but seems to protect them from death induced by the loss of trophic support. Ca2+/CaM antagonists rescue NF-kappaB-DNA binding activity and sensitize AD cells to serum withdrawal. These observations suggest that disruption of Ca2+/CaM signaling pathway could be linked mechanistically to its pro cell survival actions, promoting enhanced proliferation or decreased cell death depending on the presence of growth-stimulatory signals.
de las Cuevas
Natividad
N
Department of Pathophysiology and Human Molecular Genetics, Centro de Investigaciones Biológicas (CSIC), Ramiro de Maeztu 9, 28040-Madrid, Spain.
Muñoz
Ursula
U
Hermida
Ofelia G
OG
Martín-Requero
Angeles
A
D000368:Aged; D000544:Alzheimer Disease / Q000097:blood / Q000473:pathology / Q000503:physiopathology*; D015153:Blotting, Western / Q000379:methods; D016022:Case-Control Studies; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D050684:E2F Transcription Factors; D024202:Electrophoretic Mobility Shift Assay / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000502:physiology*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D044967:Serum / Q000502:physiology*; D013778:Tetrazolium Salts; D013844:Thiazoles; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism*
D018797:Cell Cycle Proteins; D016895:Culture Media, Serum-Free; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D004791:Enzyme Inhibitors; D007093:Imidazoles; D016328:NF-kappa B; D013778:Tetrazolium Salts; D013844:Thiazoles; D014157:Transcription Factors; C031938:calmidazolium; C022616:thiazolyl blue