The SP4 sub-project aims to increase our understanding of the molecular mechanisms by which microbial proteins interfere with cellular functions that are involved in oncogenesis. Specific objectives: Elucidate the molecular mechanisms of microbial interference with cellular pathways that control cell growth and the interaction with the microenvironment Elucidate the molecular mechanisms of microbial interference with apoptosis Elucidate the molecular mechanisms of microbial interference with the ubiquitin-proteasome system and other regulatory ubiquitin and ubiquitin-like posttranslational modification circuits that control microbial replication and cellular immortalization The continuous expression in malignant cells and/or their microenvironment of foreign proteins that interfere with critical cellular functions is a common theme in infection-associated carcinogenesis. The ubiquitin-proteasome system plays a pivotal role in the regulation of these basic cellular processes and is therefore a major target of manipulation by pathogens that need to modify the cellular environment in order to promote their ow persistence and replication. The viral and bacterial products involved in oncogenesis are often multifunctional proteins endowed with the capacity to concomitantly alter critical cellular functions such as cell cycle progression and apoptosis, differentiation and interaction with the microenvironment. Classical examples of proteins can be found in tumour viruses while very little is known on the mechanisms by which bacterial proteins may contribute to malignant transformation. Our experimental strategy is based on the assumption that a systematic dissection of the protein interaction networks affected by viral and bacterial oncoproteins and a better understanding of the molecular mechanisms by which these proteins modulate cellular functions will lead to the development of new strategies and tools for interfering with the oncogenic process. Cellular components of protein interaction networks will be identified by molecular and biochemical methods. Endpoint measurements will include monitoring of (i) cell growth and apoptosis in transfected/transduced cells in vitro and in in vivo models of oncogenesis, (ii) expression of molecules associated with cell adhesion and other types of intercellular communications. In vitro and cellular assays will be developed to assess the post-translational modification of viral and bacterial proteins by ubiquitin and ubiquitin-like molecules and the capacity of microbial proteins to promote such modifications in cellular substrates. Results obtained through these combined efforts will lead to a better understanding of the molecular mechanism by which oncogenic viral and bacterial proteins interfere with cellular functions and provide a rational basis for the development of new therapeutic strategies in infection-associated malignancies.