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. Dr. Heintz is Associate Director of the Environmental Pathology Training Grant and until 2006 served as the Leader of the Cell Signaling and Growth Control Program in the Vermont Cancer Center. His laboratory studies control of DNA synthesis and transcription during the cell cycle, with an emphasis on how enviromental agents such as reactive oxygen and nitrogen species influence cell cycle control.

Research Interests

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. 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 c-Fos, Fra-1 and E2F-6 through redox-dependent processes. 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. In a separate project, we have used high efficiency transfection techniques to introduce entire genetic loci as large as 250kb into cells, and in this fashion generated synthetic chromosomes composed entirely of only two genes (see image). We intend to use these cell lines to examine basic questions in the control of gene expression, DNA replication and chromosome structure.

A synthetic chromosome compsed of the dhfr and ERBB2 genes.

Selected Publications

Illenye, S. and Heintz, N.H. Functional analysis of bacterial artificial chromosomes in mammalian cells: mouse Cdc6 is associated with the mitotic spindle apparatus. Genomics 83:66-75, 2004.

Montigny, W., Phelps, S., Illeyne, S. and Heintz, N.H.. Parameters influencing high efficiency transfection of bacterial artificial chromosomes into cultured mammalian cells. BioTechniques 35:796-807, 2003

Yuan, Z., Schellekens, H., Warner, L., Janssen-Heininger, Y., Burch, P., Heintz, N.H. Reactive nitrogen species block cell cycle re-entry through sustained production of hydrogen peroxide. Am. J. Respir. Cell Mol. Biol. 28:705-712, 2003

Schroll, A. and Heintz, N. H . Chemical footprinting of structural and functional elements of dhfr orib during the CHOC 400 cell cycle. Gene 332:139-147, 2004.

Burch, P.M., Yuan, Z., Loonen, A. and Heintz, N.H. An ERK1,2-dependent program of chromatin trafficking of c-Fos and Fra-1 is required for cyclin D1expression during cell cycle re-entry. Mol. Cell. Biol. 24:46-96-4709, 2004.

Yuan, Z., Mossman, B. T., Taatjes, D. and Heintz, N. H. The duration of nuclear ERK1/2 signaling during cell cycle re-entry distinguishes proliferation from apoptosis in response to asbestos. Cancer Research, in press.

T. S. Rice, M. Ding, D. S. Pederson, and N. H. Heintz. The highly conserved tRNAHis guanylyltransferase Thg1p interacts with ORC and is required for the G2/M phase transition in yeast. Eukaryotic Cell 4:832-835, 2005.

P. Ranjan and N. H. Heintz. S phase arrest by reactive nitrogen species is bypassed by okadaic acid, an inhibitor of protein phosphatases PP1/PP2A. Free Radical Biology Medicine 40:24-259, 2006.

P. Ranjan, V. Anathy, P. M. Burch, K. Weirather, J. David Lambeth, and N. H. Heintz. Redox-dependent activation of cyclin D1 expression and mouse lung epithelial cell proliferation by Nox1. Antioxidants and Redox Signaling, In press.

CMB Lab Members