Superfund Research Program | Research Projects

Project 1

A Mouse Strain That Exhibits Elevated Sensitivity to Chemical Carcinogens and Hepatotoxins and the Mechanism Underlying That Increase

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Dr. Michael Karin

Project scientists are investigating the role of stress activated protein kinases in mammalian response to oxidative stress, identifying new components of this induction response, and determining the mechanism of gene induction by exposure to a few model toxicants found at Superfund sites, such as arsenite and carbon tetrachloride. The researchers are using a variety of genetic, cell biological and biochemical approaches to search for new regulatory molecules, including protein kinases and transcription factors that are involved in the oxidative stress response. The ability of such genetic alterations to affect how these animals, or cells derived from them, withstand exposure to Superfund site toxicants is being examined. Researchers are creating gene arrays, cell lines and transgenic mice that can be used as biosensors for monitoring exposure to toxicants that cause oxidative stress. Additionally, strains of mice that are deficient in activation of the protective response to oxidative stress are being created. Such mice should be supersensitive to pro-oxidants and thus will facilitate the detection and evaluation of new suspected toxicants and mixtures of chemicals from Superfund Sites for their ability to cause oxidative stress mediated toxicity.

Main Contact info

Dr. Micheal Karin
University of California, San Diego
9500 Gilman Drive Leichtag Building, Rm. 214 La Jolla, CA 92093-0723
858-534-1361

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Recent Publications and Documents

Takahashi H, Ogata H, Nishigaki R, Broide DH, Karin M. Tobacco smoke promotes lung tumorigenesis by triggering IKKb and JNK1 dependent inflammation. Cancer Cell 17:89-97, 2010
PubMed ID: 20129250

Park E, Lee J, Yu GY, He G, Ali S, Holzer R, Osterreicher C, Takahashi H, Karin M. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell 140:197-208, 2010.
PubMed ID: 20141834

Koch, K.S., Maeda, S., He, G., Karin, M, Leffert, H.L. (2009) Targeted deletion of hepatocyte IKKβ; confers growth advantages. Biochemical and Biophysical Research Communications 380:349-354
PubMed ID: 19171122

Naugler WE, Karin M. NF-KappaB and cancer-identifying targets and mechanisms. Curr Opin Genet Dev. 18(1):19-26, 2008.
PubMed ID: 18440219

Budanov AV, Karin M. p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling. Cell 134(3):451-60, 2008.
PubMed ID: 18692468

Sakurai, T., He, G., Matsuzawa, A., Yu, G.Y., Maeda, S., Hardiman, G., Karin, M. Hepatocyte necrosis induced by oxidative stress and IL-1a release mediate carcinogen-induced compensatory proliferation and liver tumorigenesis. Cancer Cell , 14: 156-65, 2008.
PubMed ID: 18691550

Sell S, Leffert HL. Liver cancer stem cells. J Clin Oncol 26(17):2800-5, 2008.
PubMed ID: 18539957

Naugler, W.E., Sakurai, T., Kim, S., Maeda, S., Kim, K., Elsharkawy, A.M., Karin, M. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science 317: 121-124, 2007.
PubMed ID: 17615358

Chang L, Kamata H, Solinas G, Luo JL, Maeda S, Venuprasad K, Liu YC, Karin M. The E3 ubiquitin ligase itch couples JNK activation to TNFalpha-induced cell death by inducing c-FLIP(L) turnover. Cell 124(3): 601-613, 2006.
PubMed ID: 16469705

Koch KS, Son KH, Maehr R, Pellicciotta I, Ploegh HL, Zanetti M, Sell S, Leffert HL. Immune-privileged embryonic Swiss mouse STO and STO cell-derived progenitor cells: major histocompatibility complex and cell differentiation antigen expression patterns resemble those of human embryonic stem cell lines. Immunology 119(1): 98-115, 2006.
PubMed ID: 16836618

Sakurai T, Maeda S, Chang L, Karin M. Loss of hepatic NF-kappa B activity enhances chemical hepatocarcinogenesis through sustained c-Jun N-terminal kinase 1 activation. Proc Natl Acad Sci U S A 103(28):10544-51, 2006.
PubMed ID: 16807293

Kamata H, Honda S, Maeda S, Chang L, Hirata H, Karin M. Reactive oxygen species promote TNFalpha-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases. Cell 120: 649-61, 2005.
PubMed ID: 15766528

Karin M and Greten FR. NF-kappaB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol 5(10): 749-59, 2005.
PubMed ID: 16175180

Maeda S, Kamata H, Luo J-L, Leffert H, Karin M. IKKbeta; Couples Hepatocyte Cell Death to Cytokine-driven Compensatory Proliferation that Promotes Chemical Hepatocarcinogenesis. Cell 121: 977-990, 2005.
PubMed ID: 15989949