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Role and regulation of p27 in neuronal apoptosis
Author(s) -
Jaiswal Surbhi,
Sharma Pushkar
Publication year - 2017
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.13918
Subject(s) - cyclin dependent kinase 5 , microbiology and biotechnology , kinase , cell cycle , biology , cyclin , cyclin dependent kinase , apoptosis , programmed cell death , cyclin dependent kinase 2 , cyclin d1 , neuroscience , protein kinase a , biochemistry
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 Aβ 42 (Amyloid β 1‐42 peptide). Co‐immunoprecipitation analysis revealed that p27 promotes interaction between Cyclin‐dependent kinase 5 (Cdk5) and cyclin D1, which is induced by Aβ 42 in 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 si RNA , restored Cdk5/p35 interaction by preventing association between Cdk5 and cyclin D1 and also abrogated Aβ 42 induced apoptosis of cortical neurons. Furthermore, analysis of cell cycle markers suggested that p27 may play a role in Aβ 42 induced 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.