Dr. Nicholas H. Heintz
Cell cycle control
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.