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Identification of Ribosomal Protein L34 as a Novel Cdk5 Inhibitor

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Abstract

The cell cycle is regulated by sequential activation, inactivation of cyclin dependent kinases (Cdk-s). Like all other Cdk-s, the catalytic subunit of Cdk5 is present in cycling cells. However, its highest concentration is found in differentiated neurons, and the only known protein that activates Cdk5 (i.e., p35) is expressed solely in the brain. Active Cdk5 is thought to be involved in thein vivophosphorylation of the neurofilament proteins and tau which are hyperphosphorylated in neurodegenerative diseases. Recent reports suggest that Cdk5 may also contribute to cellular differentiation. Therefore, it would not be unusual to surmise that there exist specific proteins that regulate Cdk5 activity in cycling cells. In order to find if this was true, a cDNA library prepared from HeLa cells was screened using the yeast-two-hybrid system. The 60S ribosomal protein, L34, was identified as a Cdk5-interacting protein. Biochemical analyses reveal that L34 cannot activate Cdk5 but potently inhibits the p35-activated kinase. L34 also interacts with Cdk4 and, in parallel, inhibits the Cdk4/cyclin D1 activity. Interestingly, L34 does not interact with Cdk2 in the two-hybrid assay nor does it inhibit the Cdk2/cyclin A enzyme. The fact that a ribosomal protein inhibits Cdk5 and Cdk4 may suggest that these two kinases have a cellular role in translational regulation.

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    Abbreviations: β-gal, beta-galactosidase; Cdk, human cyclin dependent kinase; DBD, DNA-binding domain; GSH-Sepharose, gluthathione Sepharose; GST, gluthathione-S-transferase; p35, 35 kDa protein which activates Cdk5; ORF, open reading frame; PCR, polymerase chain reaction; pRb, human retinoblastoma protein; RT, room temperature; SDS-PAGE, sodium dodecyl sulfate-polyacrylamide gel electrophoresis; TAD, transcriptional activation domain

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    Correspondence address: B. Chaudhuri, Oncology Research, Novartis Pharma AG, K-125.13.17, Basel, Switzerland. Fax: (41) (61) 696 38 35. E-mail:[email protected].

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