Enhanced proteasome-dependent degradation of the CDK inhibitor p27(kip1) in immortalized lymphocytes from Alzheimer's dementia patients.
Cyclin-dependent kinase inhibitor p27(kip1) (p27), a critical determinant for cell cycle progression, is an important regulation target of mitogenic signals. We have recently reported the existence of a molecular link between decreased p27 levels and enhanced phosphorylation of pRb protein and proliferation of immortalized lymphocytes from Alzheimer's disease (AD) patients. These cell cycle disturbances might be considered systemic manifestations, which mirror changes thought to occur in the brain, where post-mitotic neurons have been shown to display various cell cycle markers prior to degeneration. This work was undertaken to delineate the molecular mechanisms underlying the p27 down-regulation associated with AD. To this end, we evaluated the p27 protein stability in control and AD lymphoblasts. Half-life of p27 protein was markedly reduced in lymphoblasts from AD patients compared with that in control cells. The increased phosphorylation of p27 at Thr187, rather than changes in the 26S proteasome activity, is likely responsible for the enhanced degradation of p27 in AD cells. The serum-induced enhanced proliferation of AD lymphoblasts and decreased levels of p27 were abrogated by calmodulin (CaM) antagonists. The findings presented here suggest that Ca(2+)/CaM-dependent overactivation of PI3K/Akt signaling cascade in AD cells, plays an important role in regulating p27 abundance by increasing its degradation in the ubiquitin-proteasome pathway.
Muñoz
Ursula
U
Department of Cellular and Molecular Pathophysiology, Centro de Investigaciones Biológicas (CSIC), Ramiro de Maeztu 9, 28040 Madrid, Spain.
Bartolomé
Fernando
F
Bermejo
Félix
F
Martín-Requero
Angeles
A
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000097:blood / Q000201:enzymology* / Q000235:genetics; D001665:Binding Sites / Q000235:genetics / Q000276:immunology; D020013:Calcium Signaling / Q000235:genetics / Q000276:immunology; D002147:Calmodulin / Q000037:antagonists & inhibitors / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002461:Cell Line, Transformed; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D005260:Female; D006801:Humans; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D008214:Lymphocytes / Q000201:enzymology* / Q000276:immunology; D008297:Male; D009410:Nerve Degeneration / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013912:Threonine / Q000378:metabolism; D054875:Ubiquitination / Q000235:genetics / Q000276:immunology
D002147:Calmodulin; D018797:Cell Cycle Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D013912:Threonine; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D046988:Proteasome Endopeptidase Complex