Oncogenic transcription factors and their cellular targets

The principal scientific goals of our research program are the definition of the structure and function of oncogenes and their protein products, and the elucidation of the molecular pathways of cellular proliferation control and carcinogenesis. For oncogenic transcription factors, like Myc or Jun, this requires the identification of the direct and indirect target genes of these proteins. The specific aims of this project will focus on the structural and functional characterization of target genes already isolated in this laboratory, on the identification of novel targets of Myc and Jun proteins using open-system comprehensive gene expression analyses, and on further structural and dynamic analyses of transcripton factor - DNA interactions. The expression pattern of WS5, a novel gene recently isolated in this laboratory, in avian fibroblasts conditionally or non-conditionally transformed by the myc oncogene strongly suggests that it is a direct transcriptional target of the Myc protein. The entire structure of the WS5 gene and the molecular mechanisms of its transcriptional regulation will be determined. Intriguingly, WS5 is closely related to melanosomal membrane protein encoding genes strikingly overexpressed in human malignant melanoma, a tumor frequently associated with myc overexpression. The structure and transcriptional regulation of the human WS5 homologs and their deregulation in malignant melanoma will be analyzed. For the Jun targets JAC and TOJ3, isolated in this laboratory, it was unambiguously demonstrated that they have intrinsic oncogenic potential. Direct transcriptional regulation by Jun has already been proven for JAC and will be probed for TOJ3. The biochemical function of JAC and TOJ3 proteins and their specific role in jun-induced carcinogenesis will be determined. For the LIM domain protein CRP2, encoded by a target gene commonly suppressed in transformed cells, we discovered and will further analyze its specific interaction with EB1, which is also a binding partner of the tumor suppressor protein APC. We will also aim at the isolation of novel Myc and Jun targets using conditional cell transformation and open- system comprehensive gene expression analyses. Genes displaying unambiguously correlated changes in gene expression will be analyzed in detail, both for their molecular connection with the inducing oncogene and for their biochemical function. Furthermore, we will continue the analyses of the solution structure and dynamics of oncogenic transcription factor complexes and of the mechanisms of their interaction with target DNA.

The principal scientific goals of our research program are the definition of the structure and function of oncogenes and their protein products, and the elucidation of the molecular pathways of cellular proliferation control and carcinogenesis. For oncogenic transcription factors, like Myc or Jun, this requires the identification of the direct and indirect target genes of these proteins. The specific aims of this project will focus on the structural and functional characterization of target genes already isolated in this laboratory, on the identification of novel targets of Myc and Jun proteins using open-system comprehensive gene expression analyses, and on further structural and dynamic analyses of transcripton factor - DNA interactions. The expression pattern of WS5, a novel gene recently isolated in this laboratory, in avian fibroblasts conditionally or non-conditionally transformed by the myc oncogene strongly suggests that it is a direct transcriptional target of the Myc protein. The entire structure of the WS5 gene and the molecular mechanisms of its transcriptional regulation will be determined. Intriguingly, WS5 is closely related to melanosomal membrane protein encoding genes strikingly overexpressed in human malignant melanoma, a tumor frequently associated with myc overexpression. The structure and transcriptional regulation of the human WS5 homologs and their deregulation in malignant melanoma will be analyzed. For the Jun targets JAC and TOJ3, isolated in this laboratory, it was unambiguously demonstrated that they have intrinsic oncogenic potential. Direct transcriptional regulation by Jun has already been proven for JAC and will be probed for TOJ3. The biochemical function of JAC and TOJ3 proteins and their specific role in jun-induced carcinogenesis will be determined. For the LIM domain protein CRP2, encoded by a target gene commonly suppressed in transformed cells, we discovered and will further analyze its specific interaction with EB1, which is also a binding partner of the tumor suppressor protein APC. We will also aim at the isolation of novel Myc and Jun targets using conditional cell transformation and open- system comprehensive gene expression analyses. Genes displaying unambiguously correlated changes in gene expression will be analyzed in detail, both for their molecular connection with the inducing oncogene and for their biochemical function. Furthermore, we will continue the analyses of the solution structure and dynamics of oncogenic transcription factor complexes and of the mechanisms of their interaction with target DNA.