Dansen Group

 

Redox Signaling in Cancer Biology

 

foto: Tobias Dansen

PI: Tobias Dansen

Redox signaling

Redox signaling is an exciting upcoming field in cellular signal transduction. This form of signal transduction is being mediated through the (reversible) oxidation of cysteine residues within proteins by reactive oxygen species (ROS, Figure 1).

Various oxidative modifications of protein Cysteine thiols

Figure 1

Redox signaling has long been overlooked, because the cytosolic environment was thought to be too reducing for cysteines to be oxidized. It is becoming clear however, that local concentrations of hydrogen peroxide can build up that are sufficient (and required) to oxidize cysteines that are critical in protein functions[1-5]. Both positive and negative regulation of protein function by cysteine oxidation has been reported. Examples of negative regulation are for instance Protein Tyrosine Phosphatases (PTPs), which become oxidized on their catalytic cysteine, resulting in enhanced tyrosine kinase signaling. It has been suggested that this mode of inactivation of PTPs is critical for for instance insulin signaling, which is to this end accompanied by the production of hydrogen peroxide through NADPH oxidases[7-9]. An example of positive regulation by cysteine oxidation is the Nrf2 transcription factor. This transcription factor is continuously being ubiquitinylated by Cul-3 and subsequently degraded in the proteasome. Hereto Cul-3 requires binding of the Keap1 adaptor protein to Nrf-2. When cysteines in Keap1 become oxidized, Nrf2 is released, no longer degraded and can travel to the nucleus to perform its transcriptional function: the activation of antioxidant genes[10]. Another example of redox signaling is the ROS induced cysteine-thiol disulfide mediated heterodimerization of for instance FoxO and p300, which we recently reported on[11]. Hence, cysteine oxidation serves as a means to sense the local redox state and enables the cell to respond accordingly (Figure 2).

Differantial cellular respone to increasing ROS levels

Figure 2

 

Our aim

A disturbed cellular redox state has been implicated in several age-related diseases including Alzheimer's, Parkinson's, Rheumatoid arthritis and cancer. It is our aim to study how altered redox signaling contributes to cellular dysfunction and uncontrolled proliferation. We use a wide range of techniques including live fluorescence microscopy, FRAP, flow-cytometry, mass-spectrometry and 'classical' biochemistry. Model systems include tissue culture and the roundworm Caenorhabditis elegans.

Cited Literature

1 Poole, L. B., Karplus, P. A. & Claiborne, A. Protein sulfenic acids in redox signaling. Annu Rev Pharmacol Toxicol 44, 325-347 (2004).
2 D'Autreaux, B. & Toledano, M. B. ROS as signalling molecules: mechanisms that generate specificity in ROS homeostasis. Nat Rev Mol Cell Biol 8, 813-824 (2007).
3 Rhee, S. G. Cell signaling. H2O2, a necessary evil for cell signaling. Science 312, 1882-1883 (2006).
4 Veal, E. A., Day, A. M. & Morgan, B. A. Hydrogen peroxide sensing and signaling. Mol Cell 26, 1-14 (2007).
5 Finkel, T. Signal transduction by rective oxygen species. J. Cell Biol. 194(1), 7-15 (2011).
6 Tonks, N. K. Redox redux: revisiting PTPs and the control of cell signaling. Cell 121, 667-670 (2005).
7 Mahadev, K. et al. The NAD(P)H oxidase homolog Nox4 modulates insulin-stimulated generation of H2O2 and plays an integral role in insulin signal transduction. Mol Cell Biol 24, 1844-1854 (2004).
8 Bashan, N., Kovsan, J., Kachko, I., Ovadia, H. & Rudich, A. Positive and negative regulation of insulin signaling by reactive oxygen and nitrogen species. Physiol Rev 89, 27-71 (2009).
9 Loh, K. et al. Reactive oxygen species enhance insulin sensitivity. Cell Metab 10, 260-272 (2009).
10 Itoh, K., Mimura, J. & Yamamoto, M. Discovery of the Negative Regulator of Nrf2, Keap1: A Historical Overview. Antioxid Redox Signal, doi:10.1089 (2010).
11 Dansen, T. B. et al. Redox-sensitive cysteines bridge p300/CBP-mediated acetylation and FoxO4 activity. Nat. Chem. Biol. 5, 664-672 (2009)

Research in the Dansen group is being sponsored by grants from KWF Kankerbestrijding/Dutch Cancer Society and NWO ECHO.