p35, the neuronal-specific activator of cyclin-dependent kinase 5 (Cdk5) is degraded by the ubiquitin-proteasome pathway.

Titlep35, the neuronal-specific activator of cyclin-dependent kinase 5 (Cdk5) is degraded by the ubiquitin-proteasome pathway.
Publication TypeJournal Article
Year of Publication1998
AuthorsPatrick GN, Zhou P, Kwon YT, Howley PM, Tsai LH
JournalJ Biol Chem
Date Published1998 Sep 11
KeywordsAcetylcysteine, Animals, Cells, Cultured, Cerebral Cortex, COS Cells, Cyclin-Dependent Kinase 5, Cyclin-Dependent Kinases, Cysteine Endopeptidases, Embryo, Mammalian, Enzyme Activation, Enzyme Inhibitors, Half-Life, Humans, Kinetics, Mammals, Mice, Multienzyme Complexes, Nerve Tissue Proteins, Neurons, Polymerase Chain Reaction, Proteasome Endopeptidase Complex, Protein-Serine-Threonine Kinases, Purines, Rats, Rats, Sprague-Dawley, Recombinant Proteins, Roscovitine, Sequence Deletion, Transfection, Ubiquitins

Cyclin-dependent kinase 5 (Cdk5) was originally isolated by its close homology to the human CDC2 gene, which is a key regulator of cell cycle progression. However, unlike other Cdks, the activity of Cdk5 is required in post-mitotic neurons. The neuronal-specific p35 protein, which shares no homology to cyclins, was identified by virtue of its association and activation of Cdk5. Gene targeting studies in mice have shown that the p35/Cdk5 kinase is required for the proper neuronal migration and development of the mammalian cortex. We have investigated the regulation of the p35/Cdk5 kinase. Here we show that p35, the activator of Cdk5, is a short-lived protein with a half-life (t1/2) of 20 to 30 min. Specific proteasome inhibitors such as lactacystin greatly stabilize p35 in vivo. Ubiquitination of p35 can be readily demonstrated in vitro and in vivo. Inhibition of Cdk5 activity by a specific Cdk inhibitor, roscovitine, or by overexpression of a dominant negative mutant of Cdk5 increases the stability of p35 by 2- to 3-fold. Furthermore, phosphorylation mutants of p35 also stabilize p35 2- to 3-fold. Together, these observations demonstrate that the p35/Cdk5 kinase can be subject to rapid turnover in vivo and suggest that phosphorylation of p35 upon Cdk5 kinase activation plays a autoregulatory role in p35 degradation mediated by ubiquitin-mediated proteolysis.

Alternate JournalJ Biol Chem
PubMed ID9727024
Grant ListGM53049 / GM / NIGMS NIH HHS / United States
R01-CA 64888-3 / CA / NCI NIH HHS / United States
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