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Molecular pathogenesis of infection with human tumorviruses: interaction of viral genes with cellular targets

Objective

-To identify and characterize the main cellular targets for proteins encoded by the human viruses EBV, adenovirus, HPV-16 and HTLV-I
-To investigate the interference of viral proteins with cellular signal transduction and cell cycle regulatory pathways
-To study the influence of viral gene products on cellular gene expression and cell differentiation
-To analyze the potential of viral proteins to modulate the apoptotic response of their host cells

Summary:
Viral infection is involved in the pathogenesis of several cancers in humans. Among those, malignancies associated with human papillomaviruses, Epstein-Barr virus and human T-cell leukemia virus are of significant clinical importance, and particularly as secondary infections in immunosuppressed patients. We plan to analyze the molecular basis for the pathogenic effects of these viruses, which is largely unknown. There is evidence that infection by these viruses' influences a number of regulatory pathways, which control proliferation, differentiation, and survival of the host cells. Several cellular targets have now been identified for each of these viruses: Viral oncoproteins have been shown to interfere with various signal transduction pathways, to inactivate growth-suppressive nuclear proteins by direct binding, and to modulate the expression of key cell cycle regulatory genes. Furthermore, some viral oncogenes act by modulating the function of pS3, thereby influencing the apoptotic response of their host cells. Although some of these interactions have been analysed in considerable detail, a systematic analysis of these interactions is lacking. It is a major objective of the present proposal to analyse the possibility that common pathways are used by the different viruses to override growth control.

Special attention will be devoted to a molecular analysis of the interaction of viral proteins with nuclear targets, including pS3, the pRb family, and the transcription factors E2F, NF-kB and RBP-Jk. Similarly, the modulation of cellular signal transduction pathways by viral gene products will be analysed. By comparative analysis of the pathways used by each virus, it should be possible to obtain an integrated view of how human tumor viruses override growth control in their host cells, and determine whether these pathways are common to different viruses, or whether they are restricted to certain virus families. As a major benefit from these studies we anticipate a significant increase in our knowledge about the pathogenesis of the diseases associated with infections by these viruses in both healthy and immuno-suppressed patients. The work proposed here should lead to a better understanding of viral oncogenesis, and help to design novel diagnostic and therapeutic procedures for the virus-associated diseases.

Funding Scheme

CSC - Cost-sharing contracts

Coordinator

AUSTRIAN ACADEMY OF SCIENCES
Address
Rennweg 10
A - 6020 Innsbruck
Austria

Participants (6)

GSF-Forschungszentrum für Umwelt und Gesundheit GmbH
Germany
Address
Marchioninistraße
81377 München
ISTITUTO EUROPEO DI ONCOLOGIA SRL
Italy
Address
Via Ripamonti 435
20141 Milano
Institut Pasteur
France
Address
25,Rue Du Docteur Roux
75724 Paris
International Centre for Genetic Engineering and Biotechnology
Italy
Address
Via Padriciano 99
34012 Trieste
Rijksuniversiteit Leiden
Netherlands
Address
72,Wassenaarseweg
2300 AL Leiden
University of Wales College of Medicine
United Kingdom
Address
Heath Park
CF4 4XX Cardiff