title: Role and regulation of p27 in neuronal apoptosis.
abstract: It is necessary for the cell-cycle machinery of neurons to be suppressed to promote differentiation and maintenance of their terminally differentiated state. Reactivation of the cell cycle in response to neurotoxic insults leads to neuronal cell death and some cell-cycle-related proteins contribute to the process. p27 kip1 (p27), an inhibitor of cyclin-dependent kinases, prevents unwarranted cyclin-dependent kinase activation. In this study, we have elucidated a novel mechanism via which p27 promotes apoptosis of neurons stimulated by neurotoxic amyloid peptide Aβ42(Amyloid β1-42peptide). Co-immunoprecipitation analysis revealed that p27 promotes interaction between Cyclin-dependent kinase 5 (Cdk5) and cyclin D1, which is induced by Aβ42in cortical neurons. As a result, Cdk5 is sequestered from its neuronal activator p35 resulting in kinase deactivation. The depletion of p27, which was achieved by specific siRNA, restored Cdk5/p35 interaction by preventing association between Cdk5 and cyclin D1 and also abrogated Aβ42induced apoptosis of cortical neurons. Furthermore, analysis of cell cycle markers suggested that p27 may play a role in Aβ42induced aberrant cell cycle progression of neurons, which may result in apoptosis.These findings provide novel insights into how p27, which otherwise performs important neuronal functions, may become deleterious to neurons under neurotoxic conditions.
authors.affiliation: Eukaryotic Gene Expression Laboratory, National Institute of Immunology, New Delhi, India.
authors.forename: Surbhi
authors.initials: S
authors.lastname: Jaiswal
authors.affiliation: Eukaryotic Gene Expression Laboratory, National Institute of Immunology, New Delhi, India.
authors.forename: Pushkar
authors.initials: P
authors.lastname: Sharma
mesh_terms: D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D041681:NIH 3T3 Cells; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D016716:PC12 Cells; D010446:Peptide Fragments / Q000633:toxicity*; D018809:Proliferating Cell Nuclear Antigen / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D018809:Proliferating Cell Nuclear Antigen; C075222:amyloid beta-protein (1-42); C413374:p27 antigen
keywords: Apoptosis; Cdk5; Cyclin; neurons; p27