Research:

Reactive Oxygen Species (ROS) Signaling in Mitogenesis and Tumorigenesis
Our lab is focusing on a potential new mechanism of tumor suppression through regulation of ROS. As described below, HBP1 may be a new target of the p38 MAP kinase pathway in the homeostatic regulation of intracellular ROS. HBP1 is a p38 MAP kinase target and both HBP1 and p38 MAP kinase regulate intracellular GSH and ROS. Our current model is that GSH/p38 MAP kinase regulation of HBP1 function in turn controls growth activating pathways. The elucidation of the molecular mechanisms underlying HBP1 function may give novel insights into cancer progression. The central theme is outlined in the figure below.

Working Model of HBP1 Repression of Growth Activating Pathways. A part of this model summarizes the known mechanisms of ROS generation in mitogenesis. Growth factor receptors such as EGF and PDGF signal to rac via ras, resulting in ROS generation through rac-dependent NADPH oxidase (gp91) activation. NADPH oxidase has several required regulatory subunits, including p47 phox. HBP1 plays a central role in suppression of these pathways through repression of genes required for ROS generation such as p47 phox, as well as genes central to cell cycle progression such as cyclin D1. The p38 MAP kinase pathway is part of the intracellular homeostatic mechanism regulating the balance of ROS. Alteration of ROS, such as a decrease in GSH or increased H2O2 generation, results in activation of p38 MAP kinase.

For more details, please see the publications below.

Lab Members

Graduate Students

• Gene Huang (Nutrition) - chuang@hnrc.tufts.edu
• Mei Xiu (Nutrition) - mxiu@hnrc.tufts.edu

Recent Publications

1. Shih, H. H., Xiu, M., Berasi, S. P., Sampson, E. M., Leiter, A., Paulson, K. E., and Yee, A. S. (2001). HMG box transcriptional repressor HBP1 maintains a proliferation barrier in differentiated liver tissue. Mol Cell Biol 21, 5723-5732.
2. Tevosian, S. G., Albanese, C., Pestell, R. G., Paulson, K. E., and Yee, A. S. (2001). Negative regulation of the Wnt-beta-catenin pathway by the transcriptional repressor HBP1. Embo J 20, 4500-4511.
3. Denisova, N. A., Cantuti-Castelvetri, I., Hassan, W. N., Paulson, K. E., and Joseph, J. A. (2001). Role of membrane lipids in regulation of vulnerability to oxidative stress in PC12 cells: implication for aging. Free Radic Biol Med 30, 671-678.
4. Finlay, G. A., Thannickal, V. J., Fanburg, B. L., and Paulson, K. E. (2000). Transforming growth factor-beta 1-induced activation of the ERK pathway/activator protein-1 in human lung fibroblasts requires the autocrine induction of basic fibroblast growth factor. J Biol Chem 275, 27650-27656.
5. Palmer, H. J., Tuzon, C. T., and Paulson, K. E. (1999). Age-dependent decline in mitogenic stimulation of hepatocytes. Reduced association between Shc and the epidermal growth factor receptor is coupled to decreased activation of Raf and extracellular signal-regulated kinases. J Biol Chem 274, 11424-11430.
6. Wu, D., Mura, C., Beharka, A. A., Han, S. N., Paulson, K. E., Hwang, D., and Meydani, S. N. (1998). Age-associated increase in PGE2 synthesis and COX activity in murine macrophages is reversed by vitamin E. Am J Physiol 275, C661-668.
7. Palmer, H. J., and Paulson, K. E. (1997). Reactive oxygen species and antioxidants in signal transduction and gene expression. Nutr Rev 55, 353-361.
8. Hayek, M. G., Mura, C., Wu, D., Beharka, A. A., Han, S. N., Paulson, K. E., Hwang, D., and Meydani, S. N. (1997). Enhanced expression of inducible cyclooxygenase with age in murine macrophages. J Immunol 159, 2445-2451.

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