Mahin D. Maines Professor of Biochemistry & Biophysics, and Environmental Medicine B.A. 1964 (Ball State University) Ph.D. 1970 (University of Missouri) Burroughs Wellcome Toxicology Scholar NIH Merit Awardee (E-Mail: mahin_maines@urmc.rochester.edu)

The heme molecule is the active moiety of all cytochromes and globins; the cellular concentration of heme is regulated by the heme oxygenase system. We have identified two forms of heme oxygenase, HO-1 and HO-2. The two forms exhibit marked differences in molecular properties and are products of two different genes. HO-1 is a heat shock protein (hsp32) and highly inducible by oxidative stress. HO-2 is prominently and constitutively expressed in the brain and testes. The products of heme oxygenase activity are biologically active: carbon monoxide is a newly identified signaling molecule, which functions as nitric oxide in generation of cGMP; iron regulates the expression of certain genes, including ferritin and transferrin and NO synthase; and biliverdin is an effective antioxidant and antiviral complex. Biliverdin is reduced to bilirubin, also an antioxidant and anti-complement compound, by biliverdin reductase, a zinc finger protein, which is unique by virtue of having a dual co-factor/dual pH requirement.

Current research includes the following: molecular and genetic analysis of regulation and control of expression of heme oxygenase isozymes, using transgenic mice; examination of the role of carbon monoxide in generation of cGMP in the brain; and, the consequence of modulation of heme oxygenase activity on NO synthase--/guanylate cyclase cascade; characterization of biliverdin reductase structure and function; and the investigation of whether the reductase is a transcriptional factor.

Recent Publications

Lerner-Marmarosh N, Miralem T, Gibbs PE, Maines MD. Human biliverdin reductase is an ERK activator; hBVR is an ERK nuclear transporter and is required for MAPK signaling. Proc Natl Acad Sci U S A. 2008 May 13;105(19):6870-6875.

Tudor C, Lerner-Marmarosh N, Engelborghs Y, Gibbs PE, Maines MD. Biliverdin reductase is a transporter of haem into the nucleus and is essential for regulation of HO-1 gene expression by haematin. Biochem J. 2008 Aug 1;413(3):405-416.

Maines MD. Biliverdin reductase: PKC interaction at the cross-talk of MAPK and PI3K signaling pathways. Antioxid Redox Signal. 2007 Dec;9(12):2187-2195. Review.

Gibbs PE, Maines MD. Biliverdin inhibits activation of NF-kappaB: reversal of inhibition by human biliverdin reductase. Int J Cancer. 2007 Dec 1;121(11):2567-2574.

Lerner-Marmarosh N, Miralem T, Gibbs PE, Maines MD. Regulation of TNF-alpha-activated PKC-zeta signaling by the human biliverdin reductase: identification of activating and inhibitory domains of the reductase. FASEB J. 2007 Dec;21(14):3949-3962

Maines MD, Miralem T, Lerner-Marmarosh N, Shen J, Gibbs PE. Human biliverdin reductase, a previously unknown activator of protein kinase C betaII. J Biol Chem. 2007 Mar 16;282(11):8110-8122.

Calabrese V, Butterfield DA, Scapagnini G, Stella AM, Maines MD. Redox regulation of heat shock protein expression by signaling involving nitric oxide and carbon monoxide: relevance to brain aging, neurodegenerative disorders, and longevity. Antioxid Redox Signal. 2006 Mar-Apr;8(3-4):444-477. Review.

Ewing JF, Maines MD. 2006. Regulation and expression of heme oxygenase enzymes in aged-rat brain: age related depression in HO-1 and HO-2 expression and altered stress-response. J Neural Transm. Apr;113(4):439-454.

Maines MD. 2005. The heme oxygenase system: update 2005. Antioxid Redox Signal. Nov-Dec;7(11-12):1761-1766. Review.

Maines MD. 2005. New insights into biliverdin reductase functions: linking heme metabolism to cell signaling. Physiology (Bethesda). Dec;20:382-9. Review.

Maines MD, Gibbs PE. 2005. 30 some years of heme oxygenase: From a "molecular wrecking ball" to a "mesmerizing" trigger of cellular events. Biochem Biophys Res Commun. Sep 22; [Epub ahead of print]

Lerner-Marmarosh N, Shen J, Torno MD, Kravets A, Hu Z, Maines MD. 2005. Human biliverdin reductase: a member of the insulin receptor substrate family with serine/threonine/tyrosine kinase activity. Proc Natl Acad Sci U S A. May 17;102(20):7109-7114.

Miralem T, Hu Z, Torno MD, Lelli KM, Maines MD. 2005. 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. Apr 29;280(17):17084-17092