Cell cycle control
Dr. Heintz received his Ph.D. from the University of Vermont under the direction of Dr. Warren Schaeffer in Medical Microbiology and then conducted postdoctoral research with Dr. Joyce Hamlin at the University of Virginia. Dr. Heintz joined the faculty of the Department of Pathology in 1983, and has an adjunct appointment as Professor in the Department of Microbiology and Molecular Genetics. His laboratory studies regulation of the cell cycle in normal and cancer cells, with a focus on the role of reactive oxygen species in redox-dependent signaling pathways.
Our laboratory is interested in the molecular mechanisms that regulate cell proliferation and apoptosis in normal cells exposed to environmental agents, and in cancer cells. Presently we are concentrating on redox-dependent cell signaling pathways that regulate expression of cyclin D1 during cell cycle re-entry, and FoxM1 during malignant transformation. Our work shows that the redox status of the cell influences the location and duration of signals generated by mitogen-activated protein kinases (MAPK), and that these signals are processed in a cell autonomous fashion to dictate cell fate. During cell cycle re-entry, a dynamic program of signaling controls the subcellular trafficking, chromatin binding and activity of transcription factors such as E2F and FoxM1 through redox-dependent processes. In cancer cells we are concentrating on the role of FOXM1, a forkhead transcription factor over-expressed in many human malignancies, in regulating resistance to oxidative stress. We employ a wide variety of cell biology, imaging, and molecular techniques to identify specific signaling and gene targets affected by the redox status of the cell, and to manipulate experimental systems to test our hypotheses. We are also interested in the mechanisms by which cancer cells produce reactive oxygen species without activating apoptotic pathways, with a recent emphasis on the role of peroxiredoxins in redox signaling.
A synthetic chromosome compsed of the dhfr and ERBB2 genes.
Ranjan P, Heintz NH. S-phase arrest by reactive nitrogen species is bypassed by okadaic acid, an inhibitor of protein phosphatases PP1/PP2A. Free Radic Biol Med. 2006 Jan 15;40(2):247-59.
Ranjan P, Anathy V, Burch PM, Weirather K, Lambeth JD, Heintz NH. Redox-dependent expression of cyclin D1 and cell proliferation by Nox1 in mouse lung epithelial cells. Antioxid Redox Signal. 2006 Sep-Oct;8(9-10):1447-59.
Phalen TJ, Weirather K, Deming PB, Anathy V, Howe AK, van der Vliet A, Jönsson TJ, Poole LB, Heintz NH. Oxidation state governs structural transitions in peroxiredoxin II that correlate with cell cycle arrest and recovery. J Cell Biol. 2006 Dec 4;175(5):779-89.
Heintz NH, Janssen-Heininger YM, Mossman BT. Asbestos, lung cancers, and mesotheliomas: from molecular approaches to targeting tumor survival pathways. Am J Respir Cell Mol Biol. 2010 Feb;42(2):133-9.
Burhans WC, Heintz NH. The cell cycle is a redox cycle: linking phase-specific targets to cell fate. Free Radic Biol Med. 2009 Nov 1;47(9):1282-93.
* indicates equal contribution
Thompson JK, Westbom CM, MacPherson MB, Mossman BT, Heintz NH, Spiess P, Shukla A (2014) Asbestos modulates thioredoxin-thioredoxin interacting protein interaction to regulate inflammasome activation. Part Fibre Toxicol 11: 24.
Cunniff B, Snider GW, Fredette N, Stumpff J, Hondal RJ, Heintz NH (2014) Resolution of oxidative stress by thioredoxin reductase: Cysteine versus selenocysteine. Redox Biol 2: 475-84.
Cunniff B, Snider GW, Fredette N, Hondal RJ, Heintz NH (2013) A direct and continuous assay for the determination of thioredoxin reductase activity in cell lysates. Anal Biochem 443(1): 34-40.
Mossman BT, Shukla A, Heintz NH, Verschraegen CF, Thomas A, Hassan R (2013) New insights into understanding the mechanisms, pathogenesis, and management of malignant mesotheliomas. Am J Pathol 182(4): 1065-77.
Cunniff B, Benson K, Stumpff J, Newick K, Held P, Taatjes D, Joseph J, Kalyanaraman B, Heintz NH (2013) Mitochondrial-targeted nitroxides disrupt mitochondrial architecture and inhibit expression of peroxiredoxin 3 and FOXM1 in malignant mesothelioma cells. J Cell Physiol 228(4): 835-45.
Anathy V, Roberson E, Cunniff B, Nolin JD, Hoffman S, Spiess P, Guala AS, Lahue KG, Goldman D, Flemer S, van der Vliet A, Heintz NH, Budd RC, Tew KD, Janssen-Heininger YM (2012) Oxidative processing of latent Fas in the endoplasmic reticulum controls the strength of apoptosis. Mol Cell Biol 32(17): 3464-78.
Olson N, Hristova M, Heintz NH, Lounsbury KM, van der Vliet A (2011) Activation of hypoxia-inducible factor-1 protects airway epithelium against oxidant-induced barrier dysfunction. Am J Physiol Lung Cell Mol Physiol 301(6): L993-L1002.
Department of Pathology
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