Physiologically and non-physiologically generated reactive oxygen intermediates damage cell elements such as DNA, protein and lipids, and may be responsible for degenerative diseases, such as cancer, and the aging process. The goal of this proposal is to understand how cells prevent the potential damage by reactive oxygen. Genes that control the responses to reactive oxygen (oxidative stress) have been isolated recently. One system, the superoxide response genes (soxRS gene), has drawn a special attention since soxRS can be activated not only by superoxide, but also by nitric oxide. The soxRS genes encode two proteins, SoxR and SoxS. SoxR is considered as a redox sensor, and controls the expression of the soxS gene whose product SoxS then stimulates expression of a group of genes that encode defense functions. Recent evidence indicates that SoxR contains a [2Fe2S] cluster that is required for SoxR to 2Fe2S] cluster in SoxR, and exploring its assembly and disassembly processes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32ES005726-02
Application #
2331516
Study Section
Chemical Pathology Study Section (CPA)
Project Start
1997-02-01
Project End
Budget Start
1997-02-01
Budget End
1998-01-31
Support Year
2
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Harvard University
Department
Other Basic Sciences
Type
Schools of Public Health
DUNS #
082359691
City
Boston
State
MA
Country
United States
Zip Code
02115
Ding, H; Demple, B (2000) Direct nitric oxide signal transduction via nitrosylation of iron-sulfur centers in the SoxR transcription activator. Proc Natl Acad Sci U S A 97:5146-50
Demple, B; Hidalgo, E; Ding, H (1999) Transcriptional regulation via redox-sensitive iron-sulphur centres in an oxidative stress response. Biochem Soc Symp 64:119-28
Ding, H; Demple, B (1998) Thiol-mediated disassembly and reassembly of [2Fe-2S] clusters in the redox-regulated transcription factor SoxR. Biochemistry 37:17280-6
Hidalgo, E; Ding, H; Demple, B (1997) Redox signal transduction via iron-sulfur clusters in the SoxR transcription activator. Trends Biochem Sci 22:207-10
Bradley, T M; Hidalgo, E; Leautaud, V et al. (1997) Cysteine-to-alanine replacements in the Escherichia coli SoxR protein and the role of the [2Fe-2S] centers in transcriptional activation. Nucleic Acids Res 25:1469-75
Hidalgo, E; Ding, H; Demple, B (1997) Redox signal transduction: mutations shifting [2Fe-2S] centers of the SoxR sensor-regulator to the oxidized form. Cell 88:121-9
Ding, H; Demple, B (1997) In vivo kinetics of a redox-regulated transcriptional switch. Proc Natl Acad Sci U S A 94:8445-9
Ding, H; Hidalgo, E; Demple, B (1996) The redox state of the [2Fe-2S] clusters in SoxR protein regulates its activity as a transcription factor. J Biol Chem 271:33173-5
Ding, H; Demple, B (1996) Glutathione-mediated destabilization in vitro of [2Fe-2S] centers in the SoxR regulatory protein. Proc Natl Acad Sci U S A 93:9449-53