Retroviruses possess several biological features that differentiate them from all other infectious agents. The obligatory integration step of the retrovirus genome into the host genome has allowed these viruses to associate, modulate and alter the biology of the cell with a variety of unique mechanisms. Integration of retroviruses into the germ line of the host results in the formation of vertically transmitted “endogenous” retroviruses (ERVs). It is now becoming apparent that ERVs have often been selected as they provided evolutionary advantages to the host. Sheep Betaretroviruses provide a unique biological system to study the complex interaction between retroviruses and their hosts. Jaagsiekte sheep retrovirus (JSRV) is the causative agent of ovine pulmonary adenocarcinoma (OPA), a naturally occurring lung cancer of sheep. The JSRV Env glycoprotein is a dominant oncoprotein and its expression is sufficient to induce cell transformation in vitro and in vivo. Thus, OPA is a unique large animal model for the study of lung carcinogenesis. The sheep genome harbours at least 27 copies of ERVs highly related to JSRV (enJSRVs). Studies on enJSRVs have provided evidence supporting the idea that ERVs, exogenous retroviruses and the host have coevolved through a dynamic process throughout evolution. enJSRVs play a critical role in conceptus development and placental morphogenesis, and can block JSRV replication in vitro at both early and late stages of the replication cycle. The work presented here focuses on the study of the exogenous and endogenous JSRV Envs and their role in cell transformation and trophoblast differentiation respectively. We were able to show that: I) the JSRV Env transforms epithelial cells in vitro independently from its cellular receptor; II) both the exogenous and endogenous JSRV Envs interact with the receptor tyrosine kinase RON and that the cytoplasmic tail of the Env is the major determinant modulating the biological effects of the Env-RON interaction; III) the molecular chaperone Hsp90 regulates JSRV Env induced cell transformation, in part by downregulating Akt; and IV) OPA is a useful large animal model for the evaluation of new anti-cancer therapeutic agents. Moreover, we characterized the transforming properties, receptor usage and fusogenic activity of enJSRVs Envs to gain insight into their role in placental morphogenesis. The studies described in this thesis contributed to the understanding of JSRV induced cell transformation and the biology of enJSRVs.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:495094 |
| Date | January 2008 |
| Creators | Varela, Mariana |
| Publisher | University of Glasgow |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://theses.gla.ac.uk/117/ |
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