Ca2+/calmodulin-dependent modulation of cell cycle elements pRb and p27kip1 involved in the enhanced proliferation of lymphoblasts from patients with Alzheimer dementia.
Failure of cell cycle regulation in neurons might be critically involved in the process of neurodegeneration in Alzheimer's disease (AD). We present here evidence to support the hypothesis that cell cycle alterations occur in cells other than neurons in AD sufferers. Lymphocytes from AD patients immortalized with Epstein-Barr virus showed an enhanced rate of proliferation and increased phosphorylation of the retinoblastoma protein (pRb) and other members of the family of pocket proteins compared with cell lines derived from normal age-matched controls. The calmodulin antagonist calmidazolium, as well as W-7 and W-13, abrogated the enhanced activity of AD cells without altering the normal basal rate of proliferation. The effect of calmidazolium was accompanied by partially dephosphorylation of pRb. No changes were found in the expression levels of the G1 cyclin/Cdks complexes. However, lymphoblasts derived from AD patients showed reduced levels of the Cdk inhibitor p27(kip1), which were restored after anti-calmodulin treatment of the cultures. These observations suggest that in AD cells the enhanced rates of cell proliferation and phosphorylation of pRb and the intracellular content of p27(kip1) may be interrelated events controlled by a mechanism dependent on the Ca(2+)/calmodulin signaling pathway. The distinct functional features of lymphoblastoid cells from AD patients offer an invaluable, noninvasive tool to investigate the etiopathogenesis, and eventually, for the early diagnosis and prognosis of this devastating disease.
de las Cuevas
Natividad
N
Department of Pathophysiology and Human Molecular Genetics, Centro de Investigaciones Biológicas (CSIC), Velázquez 144, 28006, Madrid, Spain.
Urcelay
Elena
E
Hermida
Ofelia G
OG
Saíz-Diaz
Rosa A
RA
Bermejo
Félix
F
Ayuso
Matilde S
MS
Martín-Requero
Angeles
A
D000368:Aged; D000544:Alzheimer Disease / Q000503:physiopathology*; D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000187:drug effects / Q000378:metabolism; D002147:Calmodulin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000187:drug effects / Q000378:metabolism*; D003470:Culture Media / Q000494:pharmacology; D056746:Cyclin G; D056766:Cyclin G1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000096:biosynthesis; D016213:Cyclins / Q000096:biosynthesis; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004854:Herpesvirus 4, Human; D006801:Humans; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000502:physiology*; D010766:Phosphorylation; D016160:Retinoblastoma Protein / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D025521:Tumor Suppressor Proteins / Q000187:drug effects / Q000378:metabolism
C534702:CCNG1 protein, human; D002147:Calmodulin; D018797:Cell Cycle Proteins; D003470:Culture Media; D056746:Cyclin G; D056766:Cyclin G1; D016213:Cyclins; D004791:Enzyme Inhibitors; D016160:Retinoblastoma Protein; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D018844:Cyclin-Dependent Kinases; D002118:Calcium