Redox Signaling in Cancer Biology
PI: Tobias Dansen
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).
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. 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. Hence, cysteine oxidation serves as a means to sense the local redox state and enables the cell to respond accordingly (Figure 2).
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.
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Research in the Dansen group is being sponsored by grants from KWF Kankerbestrijding/Dutch Cancer Society and NWO ECHO.