This is a continuation application for a long-term project on effects of trace metal ions on gene expression in human cells. During the last period, we began to investigate the effects of toxic metal ions on signal transduction pathways used for global regulation of gene expression, cell proliferation and survival. The tumor promoter arsenite (As+3) was found to be a potent activator of two mitogen activated protein kinase (MAPK) cascades that stimulate the activity of transcription factor AP-1. This effect of As+3 is due to inhibition of a dual-specificity protein phosphatase, JNK phosphatase, whose normal function is to keep the MAPKs, JNK and p38 in a low activity state. As induction of AP-1 activity is closely linked to tumor promotion, the JNK phosphatase is probably an important mediator of As+3 cocarcinogenesis. It may also be involved in As+3 induced inflammatory disease. To examine the physiological role of the JNK phosphatase we will characterize and molecularly identify it using a combination of biochemical and molecular biological approaches. Dominant-negative mutants will be transfected into cultured cell lines to inhibit endogenous JNK phosphatase activity and thus assess its function in cell physiology. We will also examine the susceptibility of mouse strains and cell lines deficient in JNK or JNK phosphatase to As+3 induced cocarcinogenesis and toxicity. As+3 and other trace metals were also proposed to act through non-specific induction of oxidant stress. We therefore started to investigate the regulation of transcription factor NF-KB, which was proposed to be a major sensor of oxidant stress. We recently purified and cloned a key component in the pathway leading to NF-KB activation, the protein kinase responsible for phosphorylation and eventual degradation of the inhibitors of NF-KB, the IKBs. We now propose to study the molecular mechanism by which oxidants lead to activation of this IKB kinase (IKK). As NF-KB plays a key role in inflammation, understanding the regulation of IKK activity by oxidants, such as ozone, will provide a molecular basis for oxidant induced inflammatory disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37ES004151-22
Application #
7216814
Study Section
Special Emphasis Panel (ZRG4-ALTX-1 (01))
Program Officer
Balshaw, David M
Project Start
1986-01-01
Project End
2009-03-31
Budget Start
2007-04-01
Budget End
2009-03-31
Support Year
22
Fiscal Year
2007
Total Cost
$360,308
Indirect Cost
Name
University of California San Diego
Department
Pharmacology
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Sakurai, Toshiharu; Kudo, Masatoshi; Umemura, Atsushi et al. (2013) p38? inhibits liver fibrogenesis and consequent hepatocarcinogenesis by curtailing accumulation of reactive oxygen species. Cancer Res 73:215-24
Holzer, Ryan G; Park, Eek-Joong; Li, Ning et al. (2011) Saturated fatty acids induce c-Src clustering within membrane subdomains, leading to JNK activation. Cell 147:173-84
Sakurai, Toshiharu; He, Guobin; Matsuzawa, Atsushi et al. (2008) Hepatocyte necrosis induced by oxidative stress and IL-1 alpha release mediate carcinogen-induced compensatory proliferation and liver tumorigenesis. Cancer Cell 14:156-65
Cho, Ik-Hyun; Hong, Jinpyo; Suh, Eun Cheng et al. (2008) Role of microglial IKKbeta in kainic acid-induced hippocampal neuronal cell death. Brain 131:3019-33
Budanov, Andrei V; Karin, Michael (2008) p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling. Cell 134:451-60
Naugler, Willscott E; Karin, Michael (2008) NF-kappaB and cancer-identifying targets and mechanisms. Curr Opin Genet Dev 18:19-26
Naugler, Willscott E; Sakurai, Toshiharu; Kim, Sunhwa et al. (2007) Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science 317:121-4
Temkin, Vladislav; Karin, Michael (2007) From death receptor to reactive oxygen species and c-Jun N-terminal protein kinase: the receptor-interacting protein 1 odyssey. Immunol Rev 220:8-21
Solinas, Giovanni; Vilcu, Cristian; Neels, Jaap G et al. (2007) JNK1 in hematopoietically derived cells contributes to diet-induced inflammation and insulin resistance without affecting obesity. Cell Metab 6:386-97
Gallagher, Ewen; Enzler, Thomas; Matsuzawa, Atsushi et al. (2007) Kinase MEKK1 is required for CD40-dependent activation of the kinases Jnk and p38, germinal center formation, B cell proliferation and antibody production. Nat Immunol 8:57-63

Showing the most recent 10 out of 60 publications