Research Group BURGERING/DANSEN

Faculty of Medicine, University Medical Centre Utrecht, Dept. Molecular Cancer Research
Contact: Prof. Boudewijn Burgering
E-mail: b.m.t.burgering@umcutrecht.nl
Website: http://groups.mcr.umcutrecht.nl/burgering/

General research focus: Signalling by the PI-3 kinase/PKB/Foxo pathway

Our group is interested in signal transduction through the pathway consisting of the lipid kinase PI3K, the serine/threonine kinase PKB/AKT and members of the Forkhead boxO (FOXO) class of transcription factors. Activity of this pathway affects lifespan of organisms, but deregulation of this pathway is also causally involved in the onset of age-related diseases, especially cancer and diabetes. As such this pathway provides unique opportunities to understand the role of lifespan in the onset of disease and the trade-off between these. We are trying to understand this trade-off through detailed biochemical and analysis as well as through genetics for example in mice and C. elegans.

One of the best studied examples of a trade-off between lifespan and disease concerns that of tumor suppression and ageing. We study this trade-off by analysis of stress signaling through FOXO.

Eukaryotic life is largely dependent on oxygen for energy production. Human cells are therefore continuously being exposed to reactive oxygen species (ROS), as a byproduct of oxygen consumption. ROS can be damaging, leading to dysfunction of proteins and cells, and these deleterious effects have been implicated in the pathophysiology of diseases associated with ageing like Alzheimer’s, Parkinson’s and cancer. When cells encounter potentially toxic levels of ROS, a decision has to be made to either 1) repair the damage and go on with life, with the risk of propagating hazardous mutations 2) induce programmed cell death (apoptosis) to remove the defective cell, but this also leads to loss of tissue function 3) induce a state of permanent cell cycle arrest (senescence), which also is though to be a major cause of the ‘aged phenotype’. Hence, all three options for dealing with ROS induced damage have their pros and cons in the light of balancing tumor suppression and healthy ageing.

A key component in sensing ROS levels and subsequently making a decision as to how to respond to these levels of ROS by stimulating a transcriptional program is the FOXO family of transcription factors. Indeed, in animal model systems FOXO function has been shown to regulate healthy lifespan and tumor suppression.
Our laboratory is interested in how signals are transduced from ROS to FOXO and how these signals then lead to a specific transcriptional output.
Over the years we have found that these signals can comprise of post-translational modifications (PTMs) on FOXO that are transduced by insulin signaling, stress activated kinases like JNK, and cysteine redox reactions. We are currently linking these PTMs to FOXO’s transcriptional regulation of specific cellular programs. With this information we wish to gain insight in the regulation of the trade-off between tumor suppression and healthy lifespan.
A broad variety of techniques is used in our lab including ‘classical’ biochemistry, genomic (microarray) and proteomic (mass spec) profiling, advanced fluorescence microscopy and cytometry. These techniques are applied to both cell lines and animal model systems.

Selected publications Dansen/Burgering:
Dansen TB, Burgering BM. (2008) Unravelling the tumor-suppressive functions of FOXO proteins. Trends Cell Biol. 18(9):421-9.
Dansen TB, Smits LM, van Triest MH, de Keizer PL, van Leenen D, Koerkamp MG, Szypowska A, Meppelink A, Brenkman AB, Yodoi J, Holstege FC, Burgering BM. (2009) Redox-sensitive cysteines bridge p300/CBP-mediated acetylation and FoxO4 activity. Nat Chem Biol. 5(9):664-72.
van der Horst A, Burgering BM. (2007) Stressing the role of FoxO proteins in lifespan and disease. Nat Rev Mol Cell Biol. 8(6):440-50.
van der Horst A, de Vries-Smits AM, Brenkman AB, van Triest MH, van den Broek N, Colland F, Maurice MM, Burgering BM. (2006) FOXO4 transcriptional activity is regulated by monoubiquitination and USP7/HAUSP. Nat Cell Biol. 8(10):1064-73.
Essers MA, de Vries-Smits LM, Barker N, Polderman PE, Burgering BM, Korswagen HC. (2005) Functional interaction between beta-catenin and FOXO in oxidative stress signaling. Science. 308(5725):1181-4
Essers MA, Weijzen S, de Vries-Smits AM, Saarloos I, de Ruiter ND, Bos JL, Burgering BM. (2004) FOXO transcription factor activation by oxidative stress mediated by the small GTPase Ral and JNK. EMBO J. 23(24):4802-12.
Kops GJ, Dansen TB, Polderman PE, Saarloos I, Wirtz KW, Coffer PJ, Huang TT, Bos JL, Medema RH, Burgering BM. (2002) Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress. Nature. 419(6904):316-21

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