Understanding oncogene regulation
Cancer is believed to develop through a complex cascade of transformation events that lead to an accumulation of genetic abnormalities. Often, sequential activation of oncogenes causes pre-cancerous cells to acquire a malignant phenotype. The activating protein (AP-1) group of transcription factors consists of heterodimers of members of the c-Jun and c-Fos oncogenic protein families. Pro-inflammatory cytokines and genotoxic stress induce c-Jun phosphorylation and activation of target gene transcription. However, the precise mechanism underlying this activation process remains elusive. In order to identify factors that interact with and modulate c-Jun function depending on its phosphorylation status, the EU-funded ‘cooperation between BCL6 and c-Jun in lymphoma development and progression’ (BCL6-C-JUN-CAX) project developed a yeast three hybrid system. This method allows the analysis of protein-RNA interactions. Project scientists discovered that unphosphorylated c-Jun interacted with the Mbd3 protein and recruited the chromatin remodelling complex NuRD, mediating gene repression. Upon phosphorylation of c-Jun by Jun N-terminal kinase (JNK), this effect was relieved. Partners went a step further and generated transgenic mice with a deletion of Mbd3. These mice exhibited enhanced intestinal cell proliferation and in response to inflammation, a dramatic increase in susceptibility to colitis-induced tumourigenesis was seen. Among the target genes was the intestinal stem cell marker lgr5. The BCL6-C-JUN-CAX project findings demonstrated the importance of the JNK/c-Jun pathway in intestinal progenitor proliferation and tumourigenesis, and enhanced our understanding of how this pathway is regulated. The identification of novel pathway targets is hoped to lead to new drugs for the prevention of intestinal cancer.
