Wednesday, September 20, 2017 - 13:00 to 14:00
CTIR Sir Kenneth and Lady Noreen Murray Seminar Room
Professor Grahame Hardie FRS, FRSE, FMedSci
Professor Lluis Fajas Coll
Center for Integrative Genomics at the University of Lausanne
Cyclin dependent kinase 4 (CDK4), when associated with a D-type cyclin, regulates cell cycle entry by promoting the G1>S transition and upregulating anabolic processes such as glucose uptake and lipid synthesis. Although the roles of CDK4 and its partner cyclins in the cell cycle and cancer progression have been extensively studied, we have previously showed that CDK4 can regulate metabolic processes indirectly, through activation of the E2F1 transcription factor. Here, we report that CDK4 promotes anaerobic glycolysis and represses fatty acid oxidation in mouse embryonic fibroblasts (MEFs) by directly targeting the AMP-activated protein kinase (AMPK). We also show that fatty acid oxidation (FAO) is specifically induced by thea2-subunit-containing AMPK complexes in the MEF model. Moreover, we report that CDK4 represses FAO through direct phosphorylation and inhibition of the AMPKa2-subunit. Consistent with this, CDK4 deletion leads to a massive increase in the use of fatty acids and a decrease in non-oxidative glucose utilization. Likewise, non-phosphorylable AMPKa2 mutants and the use of a chemical CDK4 inhibitor both increase FAO rates. This novel mechanism contributes to the understanding of how CDK4 translates anabolic stimuli into ATP-consuming processes, such as proliferation, by blocking AMPK promoted catabolic processes, such as FAO.
Prof. Lluis Fajas Coll was born in Barcelona, Spain. He studied Biology at the University of Barcelona were he got his Master’s degree. He next moved to the Ernst Boehringer Institute in Vienna, Austria were he did his PhD studies. After two post-doctoral stages in France in the laboratory of Prof. Auwerx at Pasteur Institute in Lille and at the IGMM in Dr. Sardet lab in Montpellier he was recruited as Inserm associated scientist at the IGBMC in Strasbourg. He next was appointed as junior group leader with an Inserm Avenir grant in Montpellier. He is now Professor at the Center for Integrative Genomics at the University of Lausanne. The main focus of his research has been the link between cell cycle regulation, proliferation and metabolism in the context of metabolic pathologies, such as obesity and diabetes and in the context of cancer.