In vivo relevance of mTOR controlled C/EBPbeta mRNA translation for metabolic health and lifespan determination

• Applicant: Professor Dr. Cornelis F. Calkhoven
• Subject Area: Cell Biology
• Term: from 2006 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 31722218

Cancer cells maintain high metabolic rates to secure that resources and energy are plenty to survive and replicate, even under conditions when nutrients are short and cell proliferation is normally prevented. Therefore, a tumour can expand at the cost of the body, thereby contributing to the wasting syndrome that accompanies the terminal stage in cancer. Our research will address the key question of how cancer cells co-opt metabolic pathways that allow them to expand in an adverse environment. Although we rapidly are gaining insight into the pathways of metabolic signalling and their integration with growth and proliferation signals, the knowledge of how this integrated signalling is transduced into specific gene regulation and converted to a physiological response is very limited. Different protein isoforms of C/EBP¿ and -ß transcription factors, which have different functions in metabolic gene regulation and cell cycle control, are expressed by regulated mRNA-translation. Aberrant translation of C/EBP¿ and -ß mRNAs is implicated in the aetiology of a variety of cancers and our recent studies indicate that pharmacological adjustment of C/EBPß translation inhibits tumour progression. By using cell culture systems, a translation-control-reporter-system and mouse models we will examine, (1) the metabolic- and proliferation/ growth signalling pathways that cause adjustments of C/EBP¿ and -ß isoform ratios, (2) the physiological response mediated through C/EBP functions, and (3) the involvement of aberrant C/EBP translation in oncogenic conversion and its contribution to the uncoupling of proliferation/ growth and metabolic signalling pathways. The proposed research may provide the basis for the development of novel therapeutic strategies that target aberrant translational control involved in cancer or metabolic diseases.

• DFG Programme: Research Grants
• International Connection: Netherlands