MD: Tongji Medical University (1983)
PhD: Rutgers University and UMDNJ-Robert Wood Johnson Medical School (1992)
Postdoctoral Training: Stanford University School of Medicine

Joined the faculty: 2001

Affiliations: Lead Toxicologist and Team Leader, Receptor Biology Laboratory, Toxicology and Molecular Biology Branch, Health Effects Laboratory Division, NIOSH, Centers for Disease Control and Prevention

Teaching: BIOC  652, BIOC  750, BIOC  797

Phone: (304) 285-6241
Fax: (304) 285-5708
Email: qam1@cdc.gov
 

Research Interests My research seeks to understand the function and mechanism of action of xenobiotic-activated receptors (XARs) in mediating biological responses to xenochemicals, small chemicals that humans encounter from the environment including therapeutics, environmental/occupational carcinogens and toxicants, and dietary constituents. XARs consist of a large group of structurally diverse receptor/transcription factors that sense a specific change in the chemical environment of cells and coordinate the transcription of batteries of genes to eliminate the chemical stimulus, antagonize toxicity, and repair damaged tissues. Coupling of chemical sensing and gene transcription by XARs allows the cells to respond to chemical challenges rapidly and only as needed, thereby maintaining the cellular homeostasis. Aberrant XARs are associated with increased susceptibility to cancer, chemical toxicity, and certain diseases in humans and animal models. Current research is focused on analyzing the molecular aspects of three XARs.

1. The aryl hydrocarbon receptor (AhR). AhR is a ligand-activated, bHLH-PAS transcription factor. AhR mediates a broad range of adaptive and toxic responses to carcinogenic polycyclic aromatic hydrocarbons (PAHs), such as BaP, and to environmental halogenated aromatic hydrocarbons (HAHs), such as TCDD (dioxin). Induction of CYP1A1 via AhR is a critical step in the metabolic activation of BaP to ultimate carcinogens. We use CYP1A1 induction as a model to analyze the function and signal transduction of AhR. We have identified a number of factors involved in AhR action; these include the AhR-interacting protein (AIP)—a chaperone molecule that modulates ligand recognition by AhR, the TCDD-inducible poly(ADP-ribose) polymerase (TiPARP)—a PARP enzyme that is also upregulated during neuronal memory processes and tumor lymphocyte infiltration, and the AhR degradation promoting factor (ADPF)—a labile protein that negatively regulates AhR by promoting the ubiquitin-proteasomal degradation of AhR in the nucleus. A combination of molecular, biochemical, genetic, and pharmacological approaches are being used to analyze the structure and mechanism of action of these proteins in AhR signal transduction and function.
    
2. Nuclear factor erythroid 2-related factor 2 (Nrf2). Nrf2, a member of the cap ‘n’ collar bZip family of transcription factors, has recently emerged as a key regulator of cellular defense against a range of chemical and disease signals, in particular oxidative stress. Nrf2 mediates the induction of antioxidant response element (ARE)-dependent genes that include phase 2 detoxification enzymes, antioxidative proteins, and drug transporters.

   We and others have found that Nrf2 is rapidly turned over through the ubiquitin-26S proteasome pathway controlled by the Keap1/Cul3-dependent ubiquitin ligase (E3). Many inducers activate Nrf2 by binding to critical thiol groups of Keap1. We are currently analyzing the mechanism by which toxic metals, such as arsenic, and high glucose, which is the major pathogenic agent of diabetes, activate Nrf2. Mouse models with Nrf2 gene knockout are being used to analyze the functional importance of Nrf2 in metal carcinogenesis and the pathogenesis of diabetes and complications.
    

3. Metal-activated transcription factor 1 (MTF1). MTF1 is a transcription factor of the zinc finger family. Unlike most zinc finger proteins, however, MTF1 is highly regulated by zinc and a dozen of other heavy or transition metals. MTF1 mediates the induction of metallothioneins 1 and 2 (MT1, MT2) in most cell types. MTs are rich in cysteine residues and protect cells by chelating metals, quenching ROS and other reactive intermediates, and providing a reserve of zinc. Loss of MTF1 is embryonic lethal in mice suggesting a critical role of MTF1 in embryonic liver development. The molecular steps of MTF1 signal transduction remain unclear. We have found that MTF1 is subjective to inhibition by a labile repressor and that phenolic antioxidants activate MTF1 to induce MT1 via a pathway that involves mobilizing intracellular zinc pools. The current objective of research on MTF1 is to elucidate the structure and mechanism of activation of MTF1 by metals and oxidative stress.

  References:

• He, X., Kan, H., Cai, L. and Ma, Q. (2009) Nrf2 is critical in defense against high glucose-induced oxidative damage in cardiomyocytes. J Mol Cell Cardiol. 46, 47-58.
   
• Zhao, Z., He, X., Bi, Y., Xia, Y., Tao, N., Li, L. and Ma, Q. (2009) Induction of CYP4F3 by benzene metabolites in human white blood cells in vivo, in human promyelocytic leukemic cell lines, and ex vivo in human blood neutrophils. Drug Metab Dispos. 37, 282-291.
   
• Ma, Q. (2008) Xenobiotic-activated receptors: from transcription to drug metabolism to disease. Chem Res Toxicol. 21, 1651-1671.
   
• Ma, Q. and Lu, A. Y. (2008) The challenges of dealing with promiscuous drug-metabolizing enzymes, receptors and transporters. Curr Drug Metab. 9, 374-383.Ma, Q. (2008) Ah receptor: xenobiotic response meets inflammation. Blood. 112, 928-929.
   
• He, X., Chen, M. G. and Ma, Q. (2008) Activation of Nrf2 in defense against cadmium-induced oxidative stress. Chem Res Toxicol. 21, 1375-1383.
   
• Ma, Q. (2007) Aryl hydrocarbon receptor degradation-promoting factor (ADPF) and the control of the xenobiotic response. Mol Interv. 7, 133-137 Ma, Q. and Lu, A. Y. (2007) CYP1A induction and human risk assessment: an evolving tale of in vitro and in vivo studies. Drug Metab Dispos. 35, 1009-1016.