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Basic Science Research

Fumihiko Urano, MD, PhD

Dr. Urano’s extensive research on the molecular mechanisms of Endoplasmic Reticulum Stress (ER Stress) Diseases such as Alzheimer's disease, Parkinson's disease, Prion disease, ALS and Diabetes Mellitus has led to his interest in studying possible links between ER Stress and Pancreatic Cancer.

The Endoplasmic Reticulum (ER) plays an important role in incubating proteins and maturing them to full function. Since cancer cells grow and spread rapidly, they often suffer from insufficient blood supplies, resulting in areas of nutrient deprivation and hypoxia. This perturbs the sensitive environment in the ER of these cells, leading to ER stress.  To mitigate ER stress and survive, cancer cells activate stress signaling pathways, collectively known as the unfolded protein response (UPR), which counteracts ER stress. ER stress signaling is regulated by IRE1 and PERK, enzymes localized to the ER. Our preliminary results indicate not only that PERK has a function in activating the cell survival pathway through a novel component of the UPR, apoptosis antagonizing transcription factor (AATF), but that under ER stress conditions IRE1 regulates vascular endothelial growth factor-A (VEGF-A) mRNA expression, which has an important function in blood vessel formation in tumor cells. Based on these findings, we hypothesize that IRE1 and PERK signaling pathways have important functions in the survival of tumor cells, especially tumors derived from secretory cells, such as pancreatic adenocarcinoma. We are trying to target IRE1 and PERK signaling to lay the groundwork for the development of an effective means of treating pancreatic cancer.

Recent Work Includes: 

Luo, D., Yu, L., Zhang, H., He, Y., Urano, F. and Min, W. “AIP1 is critical in transducing IRE1-mediated ER stress response.”  J. Biol. Chem., in press.

Lipson, K.L., Ghosh, R. and Urano, F. “The role of IRE1a in the degradation on insulin mRNA in pancreatic beta-cells.”  PLoS One, in press.

Chambers, K.T., Unverferth, J.A., Weber, S.M., Wek, R.C., Urano, F. and Corbett, J.A. “The role of nitric oxide and the unfolded protein response in cytokine-induced beta-cell death.” Diabetes, 57(1): 124-132, 2008.

Fonseca, S.G., Lipson, K.L., and Urano, F. “Endoplasmic reticulum stress signaling in pancreatic beta-cells.” Antioxid Redox Signal., 9(12): 2335-244, 2007.

Ishigaki, S., Niwa, J.L., Yamada, S.I., Takahashi, M., Ito, T., Sone, J., Doyu, M., Urano, F., and Sobue, G. “Dorfin-CHIP chimeric proteins potently ubiquitylate and degrade familial ALS-related mutant SOD1 proteins and reduce their cellular toxicity.” Neurobiology Dis, 25(2): 331-341, 2007.

Ogata, M., Hino, S., Saito, A., Morikawa, K., Kondo, S., Kanemoto, S., Murakami, T., Taniguchi, M., Tanii, I, Yoshinaga, K., Shiosaka, S., Hammarback, J.A., Urano, F., and Imaizumi, K. “Autophagy is activated for cell survival after endoplasmic reticulum stress.” Mol Cell Biol, 26(24): 9220-9231, 2006.

Lipson, K., Fonseca, S.G., and Urano, F. “Endoplasmic reticulum stress-induced apoptosis and auto-immunity in diabetes” (Review article). Current Mol Medicine, 6(1): 71-77, 2006.

Lipson, K.L., Fonseca, S.G, Ishigaki, S., Nguyen, L.X., Foss, E., Bortell, R., Rossini, A.A., and Urano, F. “Regulation of insulin biosynthesis in pancreatic beta cells by an endoplasmic reticulum-resident protein kinase IRE1.” Cell Metabolism, 4(3): 245-254, 2006.

Fonseca, S.G.., Fukuma, M., Lipson, K., Nguyen, L.X., Allen, J.R., Oka, Y., and Urano F. “WFS1 is a novel component of the unfolded protein response and maintains ER homeostasis in pancreatic b cells.” J Biol Chem, 280(47): 39609-39615, 2005.

Kubota, K., Lee, D.H., Everett, E.T., Martinez-Mier, E.A., Snead, M.L., Nguyen, L., Urano, F., and Bartlett, J.D. “Fluoride induces ER stress in ameloblasts responsible for dental enamel formation.” J Biol Chem, 280(24): 23194-23202, 2005.

Kadowaki, H., Nishitoh, H., Urano, F., Sadamitsu, C., Matsuzawa, A., Takeda, K., Masutani, H., Yodoi, J., Urano, Y., Nagano, T. and Ichijo, H. “Amyloid beta induces neuronal cell death through ROS-mediated ASK1 activation.” Cell Death Differ, 12(1): 19-24, 2005.

Kanemoto, S., Kondo, S., Ogata, M., Murakami, T., Urano, F., and Imaizumi, K. “XBP1 activates the transcription of its target gene via an ACGT core sequence under ER stress.” Biochem Biophys Res Commun, 331(4): 1146-1153, 2005.

Allen, J.R., Nguyen, L.X., Sargent, K.E.G., Lipson, K.L., Hackett, A., and Urano, F. “High ER stress in beta cells stimulates intracellular degradation of misfolded insulin.” Biochem Biophys Res Commun, 324: 166-170, 2004.