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
Volume273
Issue37
Pagination24057-64
Date Published1998 Sep 11
ISSN0021-9258
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
Abstract

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.

DOI10.1074/jbc.273.37.24057
Alternate JournalJ Biol Chem
PubMed ID9727024
Grant ListGM53049 / GM / NIGMS NIH HHS / United States
R01-CA 64888-3 / CA / NCI NIH HHS / United States
Related Faculty: 
Pengbo Zhou, Ph.D.

Pathology & Laboratory Medicine 1300 York Avenue New York, NY 10065 Phone: (212) 746-6464
Surgical Pathology: (212) 746-2700