Cancer is a major cause of death in the United States, with the incidence of the disease increasing with each decade of life. Increased generation of reactive oxygen species (ROS) has been shown to directly initiate tumors, via both genetic and epigenetic mechanisms. Only recently, the mechanisms for epigenetic tumor promotion have begun to be identified. For example, the oncogene moxl (an NADPH oxidase) has been shown to induce ROS generation. Furthermore, ROS generation by moxl is sufficient to induce tumors without generating additional mutations. As another example, using the liver-specific transgenic c-myc/TGFa model, in which ROS generation and tumor formation are induced in the liver, treatment with the antioxidant vitamin E was sufficient to inhibit both ROS generation and tumor formation. Finally, the investigators have demonstrated that the p38 MAP kinase pathway is a regulator of intracellular glutathione biosynthesis, and is activated in response to increased ROS generation. While the components and factors regulating ROS generating pathways have been an area of intense study, the molecular mechanisms that inhibit them in normal tissues are not well understood. Thus, suppressive mechanisms are excellent candidates for the identification of new tumor suppressor genes. Given the role of the p38 MAP kinase pathway in regulating intracellular glutathione, the investigators propose to use a yeast two-hybrid experiment to clone new transcription factor targets which may regulate genes involved in ROS homeostasis. Surprisingly, they cloned HBP1, which they identified several years ago as a member of the HMG box family of DNA binding proteins. Furthermore, HBP1 is a transcriptional repressor and cell cycle inhibitor. These results immediately suggested a model in which HBP1 is a suppressor of ROS generation through the transcriptional repression of ROS-generating genes. Preliminary support for this model is that HBP1 represses the p47 phox promoter (a required component of NADPH oxidases). In this proposal, experiments are designed to probe the role of p38 MAP kinase in HBP1 transcriptional repression, and ROS-dependent growth control. Thus, the long- term goals are the mechanisms that govern normal proliferation which become aberrant in tumorigenesis.
| Berasi, Stephen P; Xiu, Mei; Yee, Amy S et al. (2004) HBP1 repression of the p47phox gene: cell cycle regulation via the NADPH oxidase. Mol Cell Biol 24:3011-24 |
| Yee, Amy S; Paulson, Eric K; McDevitt, Michael A et al. (2004) The HBP1 transcriptional repressor and the p38 MAP kinase: unlikely partners in G1 regulation and tumor suppression. Gene 336:1-13 |
| Xiu, Mei; Kim, Jiyoung; Sampson, Ellen et al. (2003) The transcriptional repressor HBP1 is a target of the p38 mitogen-activated protein kinase pathway in cell cycle regulation. Mol Cell Biol 23:8890-901 |
| Wu, Dayong; Marko, Melissa; Claycombe, Kate et al. (2003) Ceramide-induced and age-associated increase in macrophage COX-2 expression is mediated through up-regulation of NF-kappa B activity. J Biol Chem 278:10983-92 |
