On the mechanism of inhibition of p27 degradation by 15-deoxy-Delta12,14-prostaglandin J2 in lymphoblasts of Alzheimer's disease patients.
It has been proposed that neuroinflammation, among other factors, may trigger an aberrant neuronal cell cycle re-entry leading to neuronal death. Cell cycle disturbances are also detectable in peripheral cells from Alzheimer's disease (AD) patients. We previously reported that the anti-inflammatory 15- deoxy-Delta(12,14)-prostaglandin J (2) (15d-PGJ (2)) increased the cellular content of the cyclin-dependent kinase inhibitor p27, in lymphoblasts from AD patients. This work aimed at elucidating the mechanisms of 15d-PGJ (2)-induced p27 accumulation. Phosphorylation, half-life, and the nucleo-cytoplasmic traffic of p27 protein were altered by 15d-PGJ2 by mechanisms dependent on PI3K/Akt activity. 15d-PGJ (2) prevents the calmodulin-dependent Akt overactivation in AD lymphoblasts by blocking its binding to the 85-kDa regulatory subunit of PI3K. These effects of 15d-PGJ (2) were not mimicked by 9,10-dihydro-15-deoxy-Delta(12,14)- prostaglandin J (2), suggesting that 15d-PGJ (2) acts independently of peroxisome proliferator-activated receptor gamma activation and that the alpha,beta-unsaturated carbonyl group in the cyclopentenone ring of 15d-PGJ (2) is a requisite for the observed effects.
Muñoz
U
U
Department of Cellular and Molecular Pathophysiology, Centro de Investigaciones Biológicas, Madrid, Spain.
Bartolomé
F
F
Esteras
N
N
Bermejo-Pareja
F
F
Martín-Requero
A
A
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000097:blood*; D002147:Calmodulin / Q000502:physiology; D002453:Cell Cycle / Q000187:drug effects; D002478:Cells, Cultured / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D006207:Half-Life; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
C534416:15-deoxy-9,10-dihydro-delta(12,14)-prostaglandin J2; C097240:15-deoxy-delta(12,14)-prostaglandin J2; D002147:Calmodulin; D009419:Nerve Tissue Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D019869:Phosphatidylinositol 3-Kinases; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D046988:Proteasome Endopeptidase Complex; D015230:Prostaglandin D2