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Vol. 296, Issue 3, 1091-1097, March 2001
Department of Biochemistry and Biophysics, University of Rochester
School of Medicine, Rochester, New York
Biliverdin reductase catalyzes the reduction of biliverdin, the product
of heme oxygenase (HO) activity, to bilirubin. The reductase is unique
among all enzymes characterized to date in being dual
pH/cofactor-dependent. Until now the enzyme was assumed to be a
noninducible cytosolic protein. This report, for the first time,
demonstrates induction and nuclear localization of reductase in rat
kidney in response to HO-1 inducers: bacterial lipopolysaccharide (LPS)
and bromobenzene. The study also demonstrates that nuclear localization
requires an intact nuclear localization signal and is responsive to
cGMP. Specifically 16 h after treatment of rats (i.p.) with LPS (5 mg/kg), there was an increase in nuclear biliverdin reductase as
determined by immunostaining, Western blotting, and activity analysis.
Induction and nuclear localization of the reductase in kidney was also
observed in bromobenzene-treated rats (2 mmol/kg, s.c.,
24 h). The reductase message levels, however, were not increased in response to either treatment, suggesting post-transcriptional activation of the reductase by LPS and bromobenzene. The mechanism of
nuclear transport of the reductase was examined using HeLa cells
transfected with the hemagglutinin-tagged reductase construct. When
cells were treated with 8-Br-cGMP the protein translocated into the
nucleus. Mutation of the putative nuclear localization signal domain of
the reductase blocked nuclear transport of the protein. We suggest the
significance of nuclear localization of the reductase may relate to: 1)
chain-breaking antioxidant activity of bilirubin; 2) inhibition of
superoxide formation by bilirubin; and 3) modulation of the signal
transduction pathways.
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 R. Zeng, Y. Yao, M. Han, X. Zhao, X.-C. Liu, J. Wei, Y. Luo, J. Zhang, J. Zhou, S. Wang, et al. Biliverdin Reductase Mediates Hypoxia-Induced EMT via PI3-Kinase and Akt J. Am. Soc. Nephrol., February 1, 2008; 19(2): 380 - 387. [Abstract] [Full Text] [PDF]
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T. Miralem, Z. Hu, M. D. Torno, K. M. Lelli, and M. D. Maines Small Interference RNA-mediated Gene Silencing of Human Biliverdin Reductase, but Not That of Heme Oxygenase-1, Attenuates Arsenite-mediated Induction of the Oxygenase and Increases Apoptosis in 293A Kidney Cells J. Biol. Chem., April 29, 2005; 280(17): 17084 - 17092. [Abstract] [Full Text] [PDF]
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A. Kravets, Z. Hu, T. Miralem, M. D. Torno, and M. D. Maines Biliverdin Reductase, a Novel Regulator for Induction of Activating Transcription Factor-2 and Heme Oxygenase-1 J. Biol. Chem., May 7, 2004; 279(19): 19916 - 19923. [Abstract] [Full Text] [PDF]
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Z. Ahmad, M. Salim, and M. D. Maines Human Biliverdin Reductase Is a Leucine Zipper-like DNA-binding Protein and Functions in Transcriptional Activation of Heme Oxygenase-1 by Oxidative Stress J. Biol. Chem., March 8, 2002; 277(11): 9226 - 9232. [Abstract] [Full Text] [PDF]
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