The transcription factor, NFkB, is a critical factor in the cellular response to various types of stress. NFkB activation is associated with cell proliferation and occurs in many tumors. The investigators have shown that peroxisome proliferators, which cause oxidative stress and act as hepatic carcinogens in rodents, can activate NFkB in the liver. This activation can be blocked by antioxidants. NFkB activation is mediated by a signaling pathway that leads to the phosphorylation and subsequent polyubiquitination and degradation of IkB. Recently, several groups have used in vitro systems to show that the SUMO can be conjugated to IkBa in a manner that is similar to polyubiquitination of this molecule. These studies raise the interesting possibility that SUMO-modified forms of IkBa may be involved in the cellular response to stress. The investigators have identified a novel form of IkBa that is found in the livers of mice that have been treated with peroxisome proliferators. This modification is consistent with the possibility that this is a SUMO-modified form of IkBa. They hypothesize that this novel form of IkBa may be an important regulator of NFkB signaling in the livers of mice treated with peroxisome proliferators. In this grant, they propose to characterize the slower migrating form of IkBa in the livers of mice treated with peroxisome proliferators and determine whether this indeed is due to SUMO-modification. In addition, since this novel IkBa form is induced by long-term treatment with peroxisome proliferators, which are known to cause oxidative stress, the investigators will determine whether this novel IkBa can be modulated by dietary antioxidants. Overall, these studies may help elucidate additional mechanisms that control NFkB activity in organisms.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Small Research Grants (R03)
Project #
1R03ES011526-01
Application #
6447917
Study Section
Special Emphasis Panel (ZES1-BKW-C (RO))
Program Officer
Maull, Elizabeth A
Project Start
2001-09-30
Project End
2003-08-31
Budget Start
2001-09-30
Budget End
2002-08-31
Support Year
1
Fiscal Year
2001
Total Cost
$72,400
Indirect Cost
Name
University of Kentucky
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
832127323
City
Lexington
State
KY
Country
United States
Zip Code
40506