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Title: Regulation of members of the angiopoietin family by Kaposi sarcoma herpesvirus
Author: Vart, R. J.
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2008
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Kaposi sarcoma herpesvirus (KSHV) is the causative agent of Kaposi sarcoma (KS), a vascular tumour of endothelial cells. The angiopoictin family arc a group of secreted glycoproteins whose members play important roles in tumour vascularisation. The primary aim of this work was to investigate how KSHV regulated members of the angiopoictin family through the construction of a selected KSHV lentiviral expression library. Angiopoietin-2 (Ang2) is an important angiogenic factor which binds to the receptor Tie2 and is up-regulated in KS. Using a constructed KSHV lcntiviral library, viral interleukin-6 (vIL6) and viral G-protein-coupled receptor (vGPCR) were found to up-regulate Ang2 in lymphatic endothelial cells (LEC). Both vIL6 and vGPCR up-regulated Ang2 in a paracrine manner and caused an up-regulation of Ang2 through the mitogen-activated protein kinase pathway. Gene expression microarray analysis identified how other factors important for Ang2 function, and other members of the angiopoietin family, were regulated by KSHV infection of LEC. Angiopoietin-like 2 (Angptl2) has been shown to be important for proper vascularisation. My aim was to investigate the regulation of Angptl2 by KSHV and to start to investigate the function of Angptl2 in KS and cancer in general. Angptl2 is up-regulated in KS and in KSHV-infected LEC and is expressed in a variety of other neoplasms however, its expression profile did not correlate with expected angiogenic factors. The KSHV encoded viral interferon regulatory factor-1 (vIRFl) up-regulated Angptll expression in LEC and vIRFl increased Angpttt promoter activity using the first 1 kb of the Angptl2 promoter. Over-expression of Angptl2 in a mouse tumorigenesis model affected tumour growth resulting in smaller and more necrotic tumours. Ang2 and Angptl2 are likely to play important roles in KS pathogenesis. These angiopoietins along with the molecular mechanisms regulating their expression might present future targets for anti-KS therapeutics.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available