Swanton, Robert Charles;
(1998)
Viral cyclin disruption of mammalian cell cycle control mechanisms.
Doctoral thesis (Ph.D.), University College London.
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Abstract
Mammalian D-type cyclins are positive regulators of the transition through the restriction point of the cell cycle. They bind to and activate the cyclin dependent kinases, cdk4 and cdk6, leading to phosphorylation of the retinoblastoma protein and the de-repression of E2F dependent genes, essential for DNA synthesis. Two classes of cyclin dependent kinase inhibitors (CKFs) inhibit cyclin D activity by different mechanisms. The first class, typified by the p2lCip1/Waf1 protein, bind directly to the cyclin and the cdk. The second, typified by the p16ink4a protein, interact with cdk4 and cdk6. Initially, this study involved establishing key residues involved in the interaction between human cyclin D1 and p21. Mutations of surface residues of cyclin D1 identified a region implicated in this interaction. The genomes of the gamma-2-herpesviruses, herpesvirus saimiri and human herpesvirus-8 both encode cyclins, bearing substantial sequence homology to the human cyclin D family. These cyclins, like their mammalian counterparts, bind to and activate cdks 4 and 6. However, sequence conservation in the p21 interacting region was found to be divergent. This lead to the intriguing possibility that the viral cyclins enhance cell cycle progression while evading mammalian inhibitory control mechanisms. The biochemical studies contained in this thesis support this hypothesis. Furthermore, the viral cyclins are resistant to the second family of cell cycle inhibitory proteins typified by Biochemical evidence supports a revised model to understand pl6 mediated inhibition. A third herpesvirus, mouse herpesvirus-68, also encodes a cyclin homologue. Although it too shares closest sequence homology to the cyclin D family, it is unable to activate cdks 4 and 6. Biochemical analysis indicates that it activates cdk2 and in this respect may behave more like cyclins E and A. This observation may shed light on the importance of different cyclin families in the control of cell division.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D. |
| Title: | Viral cyclin disruption of mammalian cell cycle control mechanisms. |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Thesis digitised by ProQuest |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10102691 |
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