Heme Oxygenase, Biliverdin Reductase & Cell Signaling
Association of EGFP-tagged PKC-δ and DsRed2-tagged hBVR in IGF-1
treated cells as determined by confocal microscopy (a) and Fluorescence
Resonance Energy Transfer coupled with Fluorescence Lifetime
Imaging Microscopy (b,c).
The protein kinases mediate eukaryotic cells' response to internal and external stimuli such as a growth and differentiation factors, hormones, drugs and chemicals. The cell signaling pathways that transduce stimuli depend on cascades of phosphorylation/ dephosphorylation events and kinase activities. The heme metabolic pathway, which converts, sequentially, heme to biliverdin plus CO, and bilirubin, reflects activities of heme oxygenase (HO) isozymes 1, 2 and 3, which constitute the HSP32 (heat shock/stress protein) family of proteins, and biliverdin reductase (BVR). Our recent studies have identified the heme metabolic pathway as a component of the cell signal transduction pathways. We have described CO as a signaling molecule; HO proteins as an intracellular
sink for NO and potentially an intracellular oxygen sensor, bilirubin and biliverdin as modulators of protein phosphorylation.
We have recently described biliverdin reductase as a new member of the dual specificity kinase (serine/threonine/tyrosine kinase) family, a leucine zipper-type transcription factor for cAMP and AP-1 regulated genes and an inhibitor of apoptosis. We are further investigating how the HO/BVR pathway modulates cell signaling and cell cycle processes.