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Herpes viral cyclin/Cdk6 complexes evade inhibition by CDK inhibitor proteins
C Swanton1, D J Mann, B Fleckenstein
1Imperial Cancer Research Fund, London, UK.
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. The activities of these holoenzymes are constrained by CDK inhibitory proteins. The importance of the restriction point is illustrated by its deregulation in many tumour cells and upon infection with DNA tumour viruses. Here we describe the properties of cyclins encoded by two herpesviruses, herpesvirus saimiri (HVS) which can transform blood lymphocytes and induce malignancies of lymphoid origin in New World primates, and human herpesvirus 8 (HHV8) implicated as a causative agent of Kaposi's sarcoma and body cavity lymphomas. Both viral cyclins form active kinase complexes with Cdk6 that are resistant to inhibition by the CDK inhibitors p16(Ink4a), p21Cip1 and 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.
Insights
Viral cyclins from herpesviruses bypass normal cell cycle controls, forming active complexes resistant to inhibitors. This suggests a role in viral oncogenesis by deregulating cell cycle progression.
Area of Science:
- Molecular Biology
- Virology
- Cell Biology
Background:
- Cell cycle progression through the restriction point is tightly regulated by cyclin-dependent kinases (CDKs) and CDK inhibitors.
- Deregulation of the restriction point is a hallmark of cancer and viral infections.
Purpose of the Study:
- To investigate the cell cycle regulatory properties of cyclins encoded by herpesvirus saimiri (HVS) and human herpesvirus 8 (HHV8).
- To determine if these viral cyclins can overcome normal cell cycle checkpoints.
Main Methods:
- Characterization of viral cyclins' kinase activity.
- Assays to test inhibition by CDK inhibitors (p16Ink4a, p21Cip1, p27Kip1).
- Ectopic expression of viral cyclins in quiescent fibroblasts to assess effects on cell cycle arrest.
Main Results:
- Viral cyclins form active kinase complexes with Cdk6.
- These complexes are resistant to inhibition by p16Ink4a, p21Cip1, and p27Kip1.
- Viral cyclin expression overrides G1 arrest and promotes cell cycle progression in fibroblasts.
Conclusions:
- Viral cyclins provide a novel mechanism for cell cycle deregulation.
- These viral proteins may contribute to the oncogenic potential of HVS and HHV8.