Protoplasma (2003) 221: 117–127 DOI 10.1007/s00709-002-0059-y Summary. Evidence is rapidly accumulating that low-activity NAD(P)H oxidases homologous to that in phagocytic cells gener- ate reactive oxygen species as signaling intermediates. In this review we discuss evidence that signaling NAD(P)H oxidases in part influence normal and malignant cell division by activating the redox-regulated transcription factor nuclear factor kB. The roles of growth-regulatory NAD(P)H oxidases in human airway smooth muscle and malignant melanoma are used as examples. Keywords: NADPH oxidase; Nuclear factor kB; NAD(P)H oxidase subunit p22 phox ; NAD(P)H oxidase subunit gp91 phox ; Superoxide anion; Melanoma. Introduction Reactive oxygen species (ROS) were once viewed only as vehicles of chemical cellular destruction but are now also appreciated to be elegant, carefully con- trolled cellular switches for signaling cascades impor- tant in cell growth, cell death, and inflammation. One potentially important source for signaling ROS is the NOX family of NAD(P)H oxidases similar but distinct from the membrane NADPH oxidase used by phago- cytes for host defense.These NOX oxidases have been cloned for homologs (NOX1, NOX3, NOX4, and NOX5, with NOX2 corresponding to gp91 phox ) and characterized by Lambeth and co-workers (Cheng et al. 2001). We will concentrate only on the impact of NOX oxidases in cellular signaling. Most investigative efforts to link NOX oxidases to cell signaling events have occurred in the area of vas- cular diseases (Griendling et al. 2000), where the sig- naling NAD(P)H oxidase has been rapidly and carefully explored in endothelium (Gorlach et al. 2000) and vascular smooth muscle (Lassegue et al. 2001). However, important functions for these NAD(P)H oxidases are rapidly emerging in other areas. A constitutively active NAD(P)H oxidase has been recently shown responsible for increased ROS production and the hyperproliferative state of skin fibroblasts cultured from patients with systemic scle- rosis (Sambo et al. 2001). Thus, NOX oxidases are likely to be important in mediating events in a number of diseases. Components of NAD(P)H oxidase signaling While a signaling role for these NAD(P)H oxidases is now generally accepted, it is still unclear which signal- ing cascades are responsible for mediating NAD(P)H oxidase effects. Signaling is best worked out in vascu- lar smooth muscle, where the NAD(P)H oxidase is thought to mediate many of the effects of angiotensin II on vascular remodeling (Griendling et al. 2000, Irani 2001). In cultured rat vascular smooth muscle cells, expression of adenovirus-linked antisense oligo- nucleotides to NOX1 significantly decreases activation of p38 mitogen-activated protein kinase (p38 MAP kinase) and the phosphatidylinositol 3 kinase(PI 3- kinase)-activated Akt/protein kinase B (Akt) stimu- lated by angiotensin II or platelet-derived growth PROTOPLASMA Printed in Austria Redox signaling of NF-kB by membrane NAD(P)H oxidases in normal and malignant cells S. S. Brar 1 , T. P. Kennedy 1, *, M. Quinn 2 , and J. R. Hoidal 3 1 Department of Internal Medicine, Carolinas Medical Center, Charlotte, North Carolina 2 Department of Veterinary Molecular Biology, Montana State University, Bozeman, Montana 3 Department of Medicine, University of Utah, Salt Lake City, Utah Received May 4, 2002; accepted July 26, 2002; published online May 21, 2003 © Springer-Verlag 2003 * Correspondence and reprints: Department of Internal Medicine, Carolinas Medical Center, P.O. Box 32861, Charlotte, NC 28232, U.S.A.