|University of Rochester|
School of Medicine & Dentistry
|Molecular Toxicology & Environmental Medicine Cluster|
|Ph.D. Program in Toxicology|
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
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.
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