News
Chaire Francqui 2011-2012 aux FUNDP à Emile Van Schaftingen
Leçon du 28 février 2012: Leçon inaugurale
Le métabolisme intermédiaire dans l’ère génomique : l’apport des génomes dans la découverte de nouvelles enzymes.
Jusqu’avant l’ère ‘génomique’, l’élucidation du métabolisme intermédiaire se basait principalement sur (1) la découverte de métabolites, suivie par (2) la découverte d’enzymes formant ou utilisant ces métabolites, et (3) par l’identification des gènes codant ces enzymes. Cette approche a bien fonctionné pour découvrir tous les éléments des voies métaboliques (quantitativement) majeures. Le séquençage des génomes permet la découverte d’enzymes dont on postulait l’existence, mais qu’on n’avait jamais pu découvrir, ou, mieux encore, de découvrir des enzymes dont on ne soupçonnait pas l’existence. Le génome humain code ainsi des centaines d’enzymes ‘putatives’, sans doute impliquées dans le métabolisme intermédiaire et dont nous ne connaissons pas la fonction précise. Trouver des stratégies pour identifier leur fonction représente un défi majeur.
Leçon du 6 mars 2012: Une nouvelle vision de la spécificité enzymatique : la répartition de métabolites fautifs !
Leçon du 13 mars 2012: La réparation des protéines, un phénomène sous-estimé et impliquant des réactions inattendues.
Leçon du 20 mars 2012: La glucokinase, une enzyme surprenante et un acteur central du métabolisme glucidique chez l’homme.
Leçon du 27 mars 2012: Le fructose-2,6-biphosphate et autres molécules de signalisation métabolique.
Programme détaillé : http://www.fundp.ac.be/facultes/medecine/
Role of the ductal transcription factors HNF6 and Sox9 in pancreatic acinar-to-ductal metaplasia
Pancreas sustains exocrine functions that are exerted by the acinar cells which produce and secrete digestive enzymes, and the ductal cells which line ducts that drain the secretions to the intestine. When pancreas is affected by inflammation (pancreatitis) acinar cells acquire the shape and structure of duct cells, a lesion called acinar-to-ductal metaplasia (ADM). Pancreatitis is a risk factor for pancreatic adenocarcinoma (PA), a deadly cancer of the pancreas. Mouse models suggest that acinar cells are the cell type at the origin of PA and consequently, that ADM is a precursor lesion of this cancer. Until now, gene regulators controlling ADM have not yet been identified.
The team of Patrick Jacquemin and Frédéric Lemaigre investigated the involvement of HNF6 and Sox9, two transcription factors normally expressed in ductal cells, play a role in development of ADM. The team found that both factors are detected in human metaplastic acinar cells associated with pancreatitis and PA. Sox9 is also expressed in invasive PA cells. Forced expression of HNF6 in acinar cells induces metaplasia, and deletion of HNF6 and Sox9 inhibits development of ADM. The team further showed that HNF6 and Sox9 activate expression of genes typically expressed in duct cells while repressing acinar gene expression in metaplastic acinar cells. These results are published in the journal "Gut".
Beyond these results, these findings indicate that HNF6 and Sox9 are functional biomarkers of ADM. The two factors may become targets for developing drugs that inhibit progression of preneoplastic stages of PA in families with genetic predisposition to pancreatitis or PA. This work also suggests that metaplastic processes found in other organs are controlled by ectopic expression of transcription factors.
Christian de Duve's latest book is out
"De Jésus à Jésus en passant par Darwin", published by Odile Jacob.
Click on the link below to see La Libre Belgique's column (October 15, 2011) "de Duve en appelle au message de Jésus":
http://www.lalibre.be/culture/livres/article/692061/de-duve-en-appelle-au-message-de-jesus.html
Hepatic stem cells
Embryonic Ductal Plate Cells Give Rise to Cholangiocytes, Periportal
Hepatocytes, and Adult Liver Progenitor Cells
The main cell types in the liver are the hepatocytes, which exert most metablic functions of the liver, and the cholangiocytes, which line ducts through which bile flows to the intestine. In the embryonic liver, it was considered that a cell population –called ductal plate cells- located around the branches of veins constituted the progenitors of the cholangiocytes, whereas a distinct cell population was considered to give rise to the hepatocytes.
The team of Frederic Lemaigre now used a genetic labeling technique which enables to mark specifically the ductal plate cells in the mouse embryonic liver, and then to follow the fate of the marked cells after birth and in the adult (Carpentier et al. Gastroenterology 2011). It was found that the ductal plate cells give rise to cholangiocytes, as expected, but also to a subpopulation of hepatocytes, thereby revealing that the ductal plate cells have wider differentiation potential than previously thought.
Moreover, the liver has the capacity to regenerate after injury. In some conditions, such regeneration depends on so-called adult hepatic stem cells, the origin of which being debated. The team has shown, using the same genetic labeling technique, that the ductal plate cells give rise to the adult hepatic stem cells, which can now be traced and investigated during liver regeneration.
Orientation-specific signalling by thrombopoietin receptor dimers
(Thrombopoietin Receptor Signals from Different Dimeric Orientations to Promote Physiologic and Pathologic Blood Formation)
Thrombopoietin (Tpo) is a cytokine produced by the liver that is critical for regulation of the formation of platelet cells, the small anucleated blood cells that derive from the cytoplasm of megakaryocytes and that prevent bleeding upon injury. Tpo also regulates the numbers of hematopoietic stem cells and other myeloid cells. The group of Stefan Constantinescu described in 2006 and 2010 mutations around the transmembrane domain of TpoR that induce different levels of receptor activation and myeloproliferative diseases in vivo (Staerk et al., Blood 2006 107(5):1864-71; Pecquet et al., Blood 2010 115(5):1037-48).
The team thought to probe whether this receptor could actually signal from several different individual dimeric conformations. To this end short (28 amino-acid) dimeric peptides were genetically fused upstream of the transmembrane domain of TpoR, in the place of the extracellular domains. A set of seven distinct dimers was obtained, which scanned all possible dimeric interfaces. The laboratory has now shown that only one dimeric orientation of TpoR is totally inactive, while others promote either normal platelet formation, myeloproliferative disorders, and, surprisingly, in one conformation the receptor induces a myelodysplastic disorder resembling another human disease (Staerk et al., EMBO J, 2011, In Press Sep 2. doi: 10.1038/emboj.2011.315.). Thus, subtle differences in cytokine receptor dimerization provide a new level of regulation of function, that is relevant for disease. This property could be exploited by partial agonists, antibodies or small molecules.
Interview with Christian de Duve at the Lindau Nobel Laureate Meeting, 2011
In this Scientific American podcast Steve Mirsky interviews 1974 Nobel laureate of physiology and medicine Christian de Duve about going from a cell biologist to a theorist on evolution and the origin of life (duration 21.25 min).
http://www.scientificamerican.com/podcast/episode.cfm?id=science-legend-christian-de-duve-11-09-09
Guido Bommer obtains a permanent FNRS position
Guido Bommer arrived at the de Duve Institute at the end of 2008 with the support of a Brains-Back-to-Brussels grant from the Region Bruxelles Capitale. He is leading a small research group investigating the role of small regulatory RNAs in different human diseases. Starting from October 2011 he will be supported by a permanent position of the FNRS.
Interferon-lambda protects epithelia against viral infection
Interferons (IFNs) are cytokines that are produced by virus-infected cells. They act on the receptor expressed by neighboring cells to transmit infection alert signals. After stimulation by IFN, cells express a series of genes that make them more resistant to subsequent viral infection.
IFN-lambda was discovered recently and appeared to have very similar activities as the previously known IFN-alpha/beta.
In a previous work, it was found by the team of Thomas Michiels that IFN-lambda acted almost exclusively on epithelial cells, in contrast to IFN-alpha/beta that acts on almost any cell type, suggesting that IFN-lambda evolved as a protection of mucosa against pathogen invasion (Sommereyns et al., PLoS Pathog. 2008 Mar 14;4(3):e1000017....). Now, work performed by the teams of Mathias Hornef (Univ. Hanover) and Peter Stäheli (Univ. Freiburg), in collaboration with our Institute have confirmed the view that IFN-lambda acted as a protection of mucosal surfaces. This work recently published in PNAS showed that IFN-lambda acts in a non-redundant way, to protect the gastro-intestinal epithelium against infection by rotavirus (Pott et al. Proc Natl Acad Sci U S A. 2011,108: 7944-9).
Lauréats Welbio à l'Institut de Duve
Jean-François COLLET
Comprendre les mécanismes rédox impliqués dans le repliement et la réparation des protéines dans l’enveloppe cellulaire: une étape vers le développement de nouveaux antibiotiques
Pierre COULIE
Exploration et analyse d’interactions inefficaces entre des cellules cancéreuses et des lymphocytes T humains
Benoît VAN den EYNDE
Etude des mécanismes d’apprêtement des antigènes et caractérisation de nouveaux sous-types de protéasome
Pierre van der BRUGGEN
Le rôle des galectines dans la régulation de la
réponse immunitaire
Emile VAN SCHAFTINGEN
La réparation de métabolites fautifs, une nouvelle vue de la spécificité enzymatique
Miikka VIKKULA
Identification de nouveaux gènes lymph/angio-géniques en utilisant le séquençage à haut débit.
