Aging and Signal transduction

Aging and Signal transduction

Projectleader/contact

Prof. Dr. Dijke ten P. (Peter) 

Principal Investigators

Dr. J.A.F. van Dam (Hans)
Dr. M.J. Goumans (Marie-jose)
Dr. B. Guigas (Bruno)
Dr. L.M. 't Hart (Leen)

Overview

Signal transduction in aging related diseases

A complex interplay between genetic predisposition and environment determines the genesis of late-onset diseases like cancer, diabetes, osteoporosis, heart- and cardiovascular diseases and neuromuscular degeneration. Signal transduction routes are main players in the (mal)adaptations of cells to metabolic and hormonal changes and hostile environments. The aim of this research program is to define the molecular mechanisms cells use for communication with their environment and each other, how signals are transduced into the interior of cells and how the ensuing changes in their behavior are effectuated. Dysregulation of these signal transduction pathways contributes to age-related diseases and their delineation will provide new avenues for therapeutic intervention. In particular, we investigate i) how perturbation of TGF-β signaling pathways contributes to cancer, vascular- and bone diseases, ii) how in relation to cancer stress-induced signal transduction pathways respond to DNA damage, iii) which molecular mechanisms underly insulin resistance and diabetes-related complications, and iv) how cardiac stem cell differentiation is controlled and to identify key determinants in cardiac regeneration. We utilize tools in molecular cell biology, biochemistry and genetics, including functional genomics, proteomics and molecular imaging approaches.

Key publications

• Deckers M, van Dinther M, Buijs J, Que I, Lowik C, van der Pluijm G, ten Dijke P. The tumor suppressor Smad4 is required for transforming growth factor-ƒÒ-induced epithelial to mesenchymal transition and bone metastasis of breast cancer cells. Cancer Res., 2006, 66:2202-9.
• Goumans MJ, Liu Z, ten Dijke P. TGF-beta signaling in vascular biology and dysfunction. Cell Res., 2009, 19(1):116-27.
• Goumans M-J, Valdimarsdottir G, Itoh S, Lebrin F, Larsson J, Mummery C, Karlsson S, ten Dijke P. ,Activin receptor-like kinase (ALK)1 is an antagonistic mediator of lateral TGFb/ALK5  signaling. Mol Cell, 2003, 12,817-28.
• Hamdi, M., Kool, J.,  Cornelissen-Steijger, P., Carlotti, F., Popeijus, H.P., van der Burgt, C., Janssen, J.M., Yasui, A., Hoeben, R.C., Terleth, C., Mullenders, L.H., and van Dam, H. DNA damage in transcribed genes induces apoptosis via the JNK pathway and the JNK-phosphatase MKP-1. Oncogene, 2005, 24, 7135-7144.
• ten Dijke P, Arthur HM. Extracellular control of TGFbeta signalling in vascular development and disease. Nat Rev Mol Cell Biol., 2007, 8(11):857-69.
• Nascimento EB, Fodor M, van der Zon GC, Jazet IM, Meinders AE, Voshol PJ, Vlasblom R, Baan B, Eckel J, Maassen JA, Diamant M, Ouwens DM. Insulin-mediated phosphorylation of the proline-rich Akt substrate PRAS40 is impaired in insulin target tissues of high-fat diet-fed rats. Diabetes, 2006, 55:3221-8.
• Stephenne X, Foretz M, Taleux N, van der Zon GC, Sokal EM, Hue L, Viollet B, Guigas B. Metformin activates AMP-activated protein kinase in primary human hepatocytes by decreasing cellular energy status. Diabetologia. 2011, in press.
• Simonis-Bik,AM, Nijpels,G, Van Haeften,TW, Houwing-Duistermaat,JJ, Boomsma,DI, Reiling,E, van Hove,EC, Diamant,M, Kramer,MH, Heine,RJ, Maassen,JA, Slagboom,PE, Willemsen,G, Dekker,JM, Eekhoff,EM, de Geus,EJ, 't Hart,LM: Gene variants in the novel type 2 diabetes loci CDC123/CAMK1D, THADA, ADAMTS9, BCL11A and MTNR1B affect different aspects of pancreatic beta cell function. Diabetes, 2010, 59(1):293-301.

Keywords

1. Signal transduction
2. Cancer
3. Obesity, Insulin Resistance and Diabetes
4. Stem cells
5. Cardiomyocyte differentiation
6. Stress Signaling and DNA Damage Response
7. Vascular and Bone Diseases
8. TGF-β, Smad, Jun, Fos and ATF transcription factors, PKB/AKT, AMPK, mTOR
9. Genetics of type 2 diabetes