MECHANISMS OF SIGNAL TRANSDUCTION
Human Biliverdin Reductase Is a Leucine Zipper-like DNA-binding Protein and Functions in Transcriptional Activation of Heme Oxygenase-1 by Oxidative Stress*

https://doi.org/10.1074/jbc.M108239200Get rights and content
Under a Creative Commons license
open access

Human biliverdin reductase (hBVR) is a serine/threonine kinase that catalyzes reduction of the heme oxygenase (HO) activity product, biliverdin, to bilirubin. A domain of biliverdin reductase (BVR) has primary structural features that resemble leucine zipper proteins. A heptad repeat of five leucines (L1–L5), a basic domain, and a conserved alanine characterize the domain. In hBVR, a lysine replaces L3. The secondary structure model of hBVR predicts an α-helix-turn-β-sheet for this domain. hBVR translated by the rabbit reticulocyte lysate system appears on a nondenaturing gel as a single band with molecular mass of ∼69 kDa. The protein on a denaturing gel separates into two anti-hBVR immunoreactive proteins of ∼39.9 + 34.6 kDa. The dimeric form, but not purified hBVR, binds to a 100-mer DNA fragment corresponding to the mouse HO-1 (hsp32) promoter region encompassing two activator protein (AP-1) sites. The specificity of DNA binding is suggested by the following: (a) hBVR does not bind to the same DNA fragment with one or zero AP-1 sites; (b) a 56-bp random DNA with one AP-1 site does not form a complex with hBVR; (c) in vitro translated HO-1 does not interact with the 100-mer DNA fragment with two AP-1 sites; (d) mutation of Lys143, Leu150, or Leu157 blocks both the formation of the ∼69-kDa specimens and hBVR DNA complex formation; and (e) purified preparations of hBVR or hHO-1 do not bind to DNA with two AP-1 sites. The potential significance of the AP-1 binding is suggested by the finding that the response of HO-1, in COS cells stably transfected with antisense hBVR, with 66% reduced BVR activity, to superoxide anion ( O2) formed by menadione is attenuated, whereas induction by heme is not affected. We propose a role for BVR in the signaling cascade for AP-1 complex activation necessary for HO-1 oxidative stress response.

Cited by (0)

Published, JBC Papers in Press, December 31, 2001, DOI 10.1074/jbc.M108239200

*

This work was supported by National Institutes of Health Grants ES04066 and ES04391.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

On leave from the Department of Biochemistry, Hamdard University, Hamdard Nagar, New Delhi 10062, India.