HORMONE AND METABOLIC RESEARCH UNIT (HORM)

Groupleader: Louis HUE
Email: huehorm.ucl.ac.be
website: www.icp.ucl.ac.be/horm/
contact: HORM
               Avenue Hippocrate 75 UCL 75.29
               1200 BRUXELLES
               Tel: +32 2/764.75.29
               Fax: +32 2/764.75.07
HORM Unit Directory (People)
Research interest  
    Tissue-specific transcription factors in developement: This group is studying the role of the Onecut (OC) transcription factors in tissue-specific gene expression and development. These factors, discovered in the laboratory, define a new class of conserved homeoproteins, with three members in mammals : HNF-6 or OC-1, OC-2 and OC-3. They display a restricted tissue distribution and the classes of genes that they regulate overlap, but do not superimpose. HNF-6 (Hepatocyte Nuclear Factor-6), the OC prototype, was identified as a factor that controls the liver-specific transcription of PFK2/FBPase2. HNF-6 stimulates transcription by at least two different mechanisms depending on the nucleotide sequence of the DNA binding site. By interacting with DNA-bound glucocorticoid receptor, HNF-6 can also inhibit glucocorticoid-induced gene transcription in a target-specific way. In adult liver, HNF-6 stimulates transcription of genes coding for enzymes of glucose metabolism, for P450 cytochromes and for secreted proteins. In the embryo, HNF-6 is expressed in the liver and pancreas where it regulates genes coding for other transcription factors. The role of HNF-6 in development has been addressed by studying Hnf6 knockout mice generated in this laboratory. The aim of their current work is to determine the mechanisms by which the OC transcription factors control development of the pancreas, liver and gastrointestinal tract, and to investigate the role of OC factors in diseases of these organs.
Leader: Frédéric P. LEMAIGRE(lemaigrehorm.ucl.ac.be)
    Signal transduction and protein phosphorylation: Our research concerns the role of protein phosphorylation in the control of metabolism by nutrients, hormones and various stresses. As a model system, we studied 6-phosphofructo-2-kinase (PFK-2) /fructose-2,6-bisphosphatase (FBPase-2). This bifunctional enzyme catalyzes the synthesis and degradation of fructose 2,6-bisphosphate, a potent stimulator of glycolysis. Fructose 2,6-bisphosphate was discovered in this Institute by Van Schaftingen, Hue and Hers in 1980 and is the most potent stimulator of 6-phosphofructo-1-kinase (PFK-1), a key enzyme of glycolysis. Fructose 2,6-bisphosphate is synthesised from fructose 6-phosphate and ATP by 6-phosphofructo-2-kinase (PFK-2). Its hydrolysis to fructose 6-phosphate and Pi is catalysed by FBPase-2. These two activities are catalysed at separate sites of a bifunctional enzyme
(PFK-2/FBPase-2) composed of two identical subunits.
     Our work has focused on the PFK-2 domain, in which we identified the amino acids involved in substrate binding and catalysis. We also proposed a model of the threedimensional structure of the PFK-2 domain, which was confirmed when the crystal structure
became available. We have characterised several PFK-2/FBPase-2 isoforms in mammalian tissues. We also cloned the corresponding mRNAs and showed that they originate from at least two genes (1). These isoforms differ in PFK-2/FBPase-2 activity ratio, kinetic properties and response to phosphorylation by protein kinases. The C-terminus of the heart (H) isozyme, contains phosphorylation sites for several protein kinases. These sites are not present in the other isozymes, such as the liver (L) isozyme, which, by contrast, contains a single phosphorylation site for the cyclic AMP-dependent protein kinase (PKA) at the N-terminus.
The concentration of fructose 2,6-bisphosphate changes in response to metabolites, hormones, growth factors, and oncogene activation . Over recent years, we made a detailed study of the molecular mechanisms responsible for the activation of heart PFK-2 by insulin and ischemia. This led to the identification of new components of the insulin signalling cascade and to a new interpretation of the Pasteur effect.
Leaders: Louis HUE(huehorm.ucl.ac.be),
                Mark H. RIDER (riderhorm.ucl.ac.be)