MOX 1--A NOVEL MITOGENIC OXIDASE

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Reactive oxygen species (ROS) are implicated as intracellular signals and may affect cell growth and tissue hypertrophy by affecting mitogenesis, apoptosis and perhaps angiogenesis. Increased levels of ROS are seen in a variety of actively growing cells including Ras-transformed cells, a variety of cancers and cells treated with growth factors such as EGF and PDGF. Vascular smooth muscle generates ROS in response to agonists, and this has been linked to cell growth and hypertrophy which is implicated in atherosclerosis and hypertension. The origin of ROS in these cells is controversial and both mitochondrial and non-mitochondrial sources have been proposed. Phagocytes generate high levels of ROS by activating the superoxide-generating respiratory burst oxidase (a.k.a. NADPH oxidase), and it has been speculated that either this oxidase or a similar enzyme accounts for ROS generation in non-phagocytic cells. We have molecularly cloned the cDNA for p65mox1, the first member of a family of novel oxidases which are related to the catalytic flavocytochrome subunit of the respiratory burst oxidase. The mox1 message shows a unique tissue distribution in non phagocytic cells including colon, prostate and vascular smooth muscle. NIH 3T3 cells expressing mox1 generate increased superoxide and show transformed properties (focus formation, anchorage-independent growth) and marked tumorigenicity in athymic mice. This study characterizes the basic biochemistry and cell biology of mox1. Specifically, we will carry out a molecular characterization of the enzyme activity, its cofactor/coenzyme requirements, and its subcellular location. We will investigate the downstream signaling pathways that link p65mox1 to cell growth and tumorigenicity. We will also investigate the wider spectrum of biological effects of p65mox1, which include mitogenesis, angiogenesis and perhaps inhibition of apoptosis, and interventions in this pathway which may be relevant to treatment of human hyperproliferative disorders such as cancer.