Background: Synthesis of biliverdin is a prominent dimension of heme oxygenase (HO) system function in cellular defense mechanisms. Biliverdin reductase (BVR) converts biliverdin to bilirubin, the major physiological antioxidant. Importantly, in the nucleus BVR, being a leucine zipper-like DNA-binding protein, can act as a transcription factor for activator protein-1 (AP-1)-regulated genes. It has been shown that BVR modulates ATF-2 and HO-1 expression, what suggests its potential role in regulation of AP-1 and cAMP-regulated genes as well and a role in cell signaling. Moreover, BVR has a capacity as a serine/ threonine/ tyrosine kinase what is unrelated to its reductase activity (Maines et al. Physiology (Bethesda). 2005; 20: 382-9). Possessing these features together makes this protein unusually interesting and unique among all enzymes characterized to date.

Methods and Results: The genetically modified line of NIH 3T3 fibroblasts has been established, containing human BVR cDNA driven by tetracycline response element (TRE), binding an inducible transcriptional activator. The latter is regulated reversibly by exposing to doxycycline. Treatment with doxycyline concentration-dependently induced the expression of human BVR, confirmed by RT-PCR, Western blot and measurement of BVR enzymatic activity. Increase in BVR expression resulted in augmentation of the expression of HO-1 and phosphorylated ERK, JNK and p38 kinases. In order to verify the involvement of BVR in the cellular resistance against oxidative stress genetically modified NIH 3T3 cells were treated with doxycyclin prior to H₂O₂ or cytotoxic drugs (cisplatin, doxorubicin). Data indicate that enhanced activity of BVR may partially protect cells against such stress conditions.

Conclusions: The activity of BVR may be of significance in tumor cells and may influence the effectiveness of therapies connected with generation of reactive oxygen species.

The work was supported by grant PBZ- KBN 107/P04/2004

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