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Herpes viral cyclin/Cdk6 complexes evade inhibition by CDK inhibitor proteins

Abstract

The passage of mammalian cells through the restriction point into the S phase of the cell cycle is regulated by the activities of Cdk4 and Cdk6 complexed with the D-type cyclins and by cyclin E/Cdk2 (refs 1,2,3). The activities of these holoenzymes are constrained by CDK inhibitory proteins4,5. The importance of the restriction point is illustrated by its deregulation in many tumour cells6,7 and upon infection with DNA tumour viruses8. Here we describe the properties of cyclins encoded by two herpesviruses, herpesvirus saimiri (HVS) which can transform blood lymphocytes9 and induce malignancies of lymphoid origin in New World primates9,10, and human herpesvirus 8 (HHV8) implicated as a causative agent of Kaposi's sarcoma and body cavity lymphomas11,12. Both viral cyclins form active kinase complexes with Cdk6 that are resistant to inhibition by the CDK inhibitors p16Ink4a, p21Cip1and p27Kip1. Furthermore, ectopic expression of a viral cyclin prevents G1 arrest imposed by each inhibitor and stimulates cell-cycle progression in quiescent fibroblasts. These results suggest a new mechanism for deregulation of the cell cycle and indicate that the viral cyclins may contribute to the oncogenic nature of these viruses.

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Figure 1: Lack of inhibition of V-cyclin/Cdk6 and K-cyclin/Cdk6 complexes by p21Cip1, p27Kip1and p16Ink4a.
Figure 2: Co-precipitation of cyclins with p21Cip1, p27Kip1and Cdk6.
Figure 3: Stimulation of quiescent cells by expression of K-cyclin.

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Acknowledgements

We thank C. Sherr and M. Meyerson for gifts of baculovirus recombinants. We thank M. Hall for technical advice on the cyclin-inhibitor binding assay and for providing purified inhibitor proteins. We also thank D. Davies and C. Hughes for help with FACS analysis, G. Clark and A.Davies for sequencing analysis, and G. Card and N. McDonald for advice and encouragement throughout the study. This study was funded by the Imperial Cancer Research Fund. C.S. is supported by University College London Medical School and F.N. by the ‘Deutsche Krebsforschungstifftung founded by Mildred Scheel’ foundation.

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Correspondence to Nic Jones.

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Swanton, C., Mann, D., Fleckenstein, B. et al. Herpes viral cyclin/Cdk6 complexes evade inhibition by CDK inhibitor proteins. Nature 390, 184–187 (1997). https://doi.org/10.1038/36606

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