Oncogenic signalling downstream of AP-1

The Jun oncoprotein represents a major component of the transcription factor complex AP-1 which regulates the expression of multiple genes essential for cell proliferation, differentiation and apoptosis. Constitutive activation of endogenous AP-1 is required for tumor formation in avian and mammalian cell transformation systems and occurs in distinct human tumor cells suggesting that AP-1 plays an important role in human oncogenesis. The highly oncogenic v-jun allele capable to induce neoplastic transformation in avian fibroblasts and fibrosarcomas in chicken as a single oncogenic event was generated by mutation of the cellular proto-oncogene c-jun during retroviral transduction. Hence, avian cells represent a suitable model system to investigate molecular mechanisms underlying Jun-induced cell transformation. Approaches aimed at the identification of genes specifically deregulated in Jun-transformed fibroblasts have led to the identification of several genes directly or indirectly targeted by oncogenic Jun. Due to the observed deregulation of multiple genes, it is assumed that only the combined differential expression of target genes or of a subset thereof contributes to the conversion of a normal fibroblast into a tumor cell displaying a phenotype typical of Jun-induced cell transformation. Recently, it has been shown that some activated targets exhibit partial transforming activity upon over-expression. In addition, there are examples that distinct target genes silenced by v-Jun inhibit cell transformation when re-expressed in v-jun- transformed cells. In this project, novel Jun targets which have been recently isolated will be tested systematically for their biological activities regarding cell transformation. Furthermore, a retroviral vector system allowing the expression of short interfering RNAs in avian cells will be developed to enable further functional testing of known transformation-associated targets. Finally, the simultaneous expression of upregulated targets and of interfering RNAs corresponding to downregulated targets will be attempted in primary fibroblasts to possibly generate a phenotype similar to that of Jun-transformed cells in order to reveal molecular pathways operating downstream of oncogenic Jun. Consequently, protein products of key target genes essential for cell transformation may be tested in the future as potential drug targets for interference with human oncogenesis in which aberrant AP-1 signalling is involved.

The Jun oncoprotein represents a major component of the transcription factor complex AP-1 which regulates the expression of multiple genes essential for cell proliferation, differentiation and apoptosis. Constitutive activation of endogenous AP-1 is required for tumor formation in avian and mammalian cell transformation systems and occurs in distinct human tumor cells suggesting that AP-1 plays an important role in human oncogenesis. The highly oncogenic v-jun allele capable to induce neoplastic transformation in avian fibroblasts and fibrosarcomas in chicken as a single oncogenic event was generated by mutation of the cellular proto-oncogene c-jun during retroviral transduction. Hence, avian cells represent a suitable model system to investigate molecular mechanisms underlying Jun-induced cell transformation. Approaches aimed at the identification of genes specifically deregulated in Jun-transformed fibroblasts have led to the identification of several genes directly or indirectly targeted by oncogenic Jun. Due to the observed deregulation of multiple genes, it is assumed that only the combined differential expression of target genes or of a subset thereof contributes to the conversion of a normal fibroblast into a tumor cell displaying a phenotype typical of Jun-induced cell transformation. Recently, it has been shown that some activated targets exhibit partial transforming activity upon over-expression. In addition, there are examples that distinct target genes silenced by v-Jun inhibit cell transformation when re-expressed in v-jun- transformed cells. In this project, novel Jun targets which have been recently isolated will be tested systematically for their biological activities regarding cell transformation. Furthermore, a retroviral vector system allowing the expression of short interfering RNAs in avian cells will be developed to enable further functional testing of known transformation-associated targets. Finally, the simultaneous expression of upregulated targets and of interfering RNAs corresponding to downregulated targets will be attempted in primary fibroblasts to possibly generate a phenotype similar to that of Jun-transformed cells in order to reveal molecular pathways operating downstream of oncogenic Jun. Consequently, protein products of key target genes essential for cell transformation may be tested in the future as potential drug targets for interference with human oncogenesis in which aberrant AP-1 signalling is involved.