The purpose of this renewal application is to continue to study the role of the ras oncogenes in induced thymic lymphomas With the results obtained in the previous period of the grant we are going to analyze the pathological alterations associated with this family of oncogenes at the molecular level. To fulfil that goal we will investigate if ras is an early or late event in this system using different modifications of the polymerase chain reaction (PCR) technique. This should provide a clue to the question of whether ras acts in initiation or progression in the process of tumor development. To approach the problem from another angle we will use our transgenic mouse lines with the N-ras oncogene to assess the degree of contribution of activated ras genes to the tumorigenic process triggered by inducing agents. We will also analyze here our recent finding that transgenic lines with the normal N-ras protooncogene also present associated malignancies. As a complement we will make N-ras constructs with promoter-enchancers that should direct expression of the oncogene to the thymus to investigate if N-ras is tumorigenic when highly expressed in T cells since there is where we initially isolated that oncogene. To understand better how ras can contribute to the tumorigenic process it is necessary to address the regulation of expression and function of the ras genes. In the previous period of the grant we have isolated and characterized a cDNA for a gene closely adjacent to N-ras and we will analyze how this spatial relationship can modulate N-ras expression and we will study the possible functional interaction, of the two gene products. Finally, we will approach the study of ras function analyzing the role of ras genes in signal transduction using the PCI2 cell system where we have already reported that ras genes seem to be involved in NGF and bFGF signal transduction. In summary, this proposal analyzes at the molecular level the role of ras oncogenes in the pathological alterations to which they have been associated, specifically tumor development. To gain a better knowledge of these processes several aspects of the ras functional pathways will be also analyzed.
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