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Enhanced proteasome-dependent degradation of the CDK inhibitor p27kip1 in immortalized lymphocytes from Alzheimer´s dementia patients

AuthorsMuñoz, Úrsula CSIC; Bartolomé Robledo, Fernando CSIC ORCID CVN; Bermejo-Pareja, Félix; Martín-Requero, Ángeles CSIC ORCID
KeywordsAlzheimer's disease
Cell proliferation
proteasome activity
Issue DateOct-2008
CitationNeurobiology of Aging, 29 (10) : 1474-1484 (2008)
AbstractCyclin-dependent kinase inhibitor p27kip1 (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 Ca2+/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
Description11 páginas, 11 figuras -- PAGS nros. 1474-1484
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