Biochemistry

Mark E. Martin

Associate Professor of Biochemistry

E-mail:martinma@missouri.edu

Office: NW301B Medical Sciences Bldg.

Mail: Biochemistry
117 Schweitzer Hall
University of Missouri
Columbia, MO 65211

Phone: 573-882-5654

Fax: 573-884-4812

Educational background

Curriculum vitae

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Notable honors and service

• American Heart Association Established Investigator, 1993
• National Institutes of Health, Director's "Shannon Award," 1993
• Order of Socrates (Medical Education Excellence, Master Teacher), University of Missouri, 2003
• Jane Hickman Teacher of the Year Award, University of Missouri School of Medicine and Medical Alumni Association, 2003

Research summary

My lab studies the functional domains of the Ets-related transcription factor GABP and transcriptional and translational regulatory mechanisms that regulate the expression of mitochondrial and cytoplasmic Glutathione Reductase.

Research description

The regulation of gene expression is a fundamental process required for growth and development of all living organisms. Transcription factors regulate gene expression by binding to specific DNA sequences in promoter regions of genes and modulating mRNA synthesis. The regulation of the activities of transcription factors is at the heart of gene regulation. RNA polymerase II (Pol II) transcribes genes from promoter sequences containing various sequence elements that determine Pol II binding and transcription initiation. Transcription Factors bind to these sequences and recruit the general transcription machinery including Pol II to the promoter. The general transcription factor TFIID, binds to the promoter element called the TATAA box present in most Pol II promoters. Promoters lacking the TATAA box, contain sequence elements called Initiators that are bound by factors that recruit TFIID and Pol II to the promoter. The GA-binding Protein, or GABP, is a unique transcription factor capable of serving as an initiator factor or a transcription factor capable of both positive and negative transcriptional activities. GABP is composed of two subunits, GABPα and GABPβ, and each subunit provides distinct functions to the complex. GABPα belongs to the Ets-family, and contains the Ets-protein domain which is necessary for DNA binding.

GABPβ, is unable to bind DNA on its own but contains an activation domain and mediates GABPα2β2 tetramer assembly during binding to two GABP binding sites. Dr. Martin's lab is working to characterize GABP tetramer assembly and define its role in transcription.
GABP regulates the expression of a number of nuclear encoded genes involved in mitochondrial oxidative phosphorylation, including mitochondrial transcription factor A (mtTF-A), which is required for transcription of mitochondrial encoded genes involved in oxidative phosphorylation. Thus, GABP provides an important link for coordinate expression of nuclear and mitochondrial encoded proteins involved in cellular energy production. Furthermore, the DNA binding activity of GABP is regulated by reactive oxygen species generated during respiration through reduction/oxidation (Redox) reactions, suggesting that GABP is a sensor of the Redox/energy state of mammalian cells. Dr. Martin's lab is characterizing the regulatory mechanisms affecting GABP initiator and activator activities and is investigating the role of GABP in maintenance of the cellular Redox state and energy metabolism.

Because GABP is such an important regulator of the expression of respiratory chain components and, thus, helps determine the overall respiratory capacity of cells, the regulation of GABP expression is critical to setting and maintaining appropriate levels of expression of respiratory chain proteins. This is particularly critical in tissues involved in high energy requiring processes including heart muscle, brain, brown adipose and liver. Dr. Martin's lab has recently isolated and characterized the promoter from the human and mouse GABPα genes. Ongoing projects will characterize potential regulatory sequences involved in regulation of GABPα expression to determine the regulatory mechanisms involved in tissue-specific expression patterns observed for GABP subunits.

The respiratory chain of mitochondria is the primary source of reactive oxygen species (ROS) in mammalian cells. The glutathione antioxidant system plays an essential role in protecting the mitochondria from the ravages of excess ROS production during oxidative stress. While mitochondrial readily obtain reduced glutathione (GSH) from the cytoplasm, oxidized glutathione (GSSG) produced during oxidative stress primarily by the action of glutathione peroxidases, cannot be exported from the mitochondrial matrix. Glutathione reductase (GSR) recycles GSSG to GSH using the reducing power of NADPH. The mitochondrial and cytoplasmic forms of GSR (mtGSR and cytGSR respectively) are encoded by the same gene through the use of two alternative in-frame translation initiation (AUG) codons. Recent observations in our lab indicate that GABP is an important regulator of GSR expression. Current studies are directed at characterizing the mechanisms of transcriptional and translational expression of the mitochondrial and cytoplasmic forms of GSR during mitochondrial biogenesis and oxidative stress.

Selected publications

Chinenov, Y., Henzl, M., and Martin, M. E. The α and β Subunits of the GA-Binding Protein Form a Stable Heterodimer in Solution: Revised Model of Heterotetrameric Complex Assembly. (2000). J. Biol. Chem. 275:7749-7756.

Chinenov, Y., Coombs, C. and Martin, M. E. Isolation of a Bi-directional Promoter directing expression of the mouse GABPα and ATP synthase coupling factor 6 genes. (2001). GENE. 261:311-320.

Patton, J., Block, S. Combs, C., and Martin, M. E. Identification of functional elements in the murine Gabpα/ATP synthase coupling factor 6 bi-directional promoter. (2006). GENE. 369:35-44