Abstract

Hypoxia-Inducible transcription factors (HIFs) are thought to regulate multiple facets of solid tumor progression. Using genetic and biochemical screens for proteins able to modify HIF-1alpha responses, we have isolated the CSN5 subunit of the COP9 Signalosome (CSN). We have further found that CSN5 associated directly and constitutively with the pVHL tumor suppressor. This proposal seeks to define the precise mechanism(s) in which CSN5 regulates pVHL-mediated HIF-alpha stability. To accomplish this we propose to: 1) test if CSN5 regulates global or specific 26S-dependent protein degradation; 2) test if CSN5 binds HIF-1a or pVHL in association with the CSN holocomplex or as a component of another protein complex and which CSN5-associated complex (es) are able to prevent HIF-la ubiquitylation; 3) test if mutations in CSN components that influence CSN assembly or activity can alter HIF-la stability; and 4) examine the mechanism(s) by which CSN5 directly alters HIF-1a stabilization. Accomplishment of these specific aims will reveal novel pathways of HIF-1alpha and pVHL regulation and will suggest potential mechanisms by which these pathways could be manipulated for therapeutic benefit.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA102301-04
Application #
7241461
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Knowlton, John R
Project Start
2004-09-01
Project End
2009-06-30
Budget Start
2007-07-01
Budget End
2009-06-30
Support Year
4
Fiscal Year
2007
Total Cost
$219,528
Indirect Cost

  Institution

Name
University of Louisville
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40292

  Publications

Rendon, Beatriz E; Willer, Sharon S; Zundel, Wayne et al. (2009) Mechanisms of macrophage migration inhibitory factor (MIF)-dependent tumor microenvironmental adaptation. Exp Mol Pathol 86:180-5
Winner, Millicent; Leng, Lin; Zundel, Wayne et al. (2007) Macrophage migration inhibitory factor manipulation and evaluation in tumoral hypoxic adaptation. Methods Enzymol 435:355-69
Winner, Millicent; Koong, Albert C; Rendon, Beatriz E et al. (2007) Amplification of tumor hypoxic responses by macrophage migration inhibitory factor-dependent hypoxia-inducible factor stabilization. Cancer Res 67:186-93
Mikus, Peter; Zundel, Wayne (2005) COPing with hypoxia. Semin Cell Dev Biol 16:462-73
Richardson, Katharine S; Zundel, Wayne (2005) The emerging role of the COP9 signalosome in cancer. Mol Cancer Res 3:645-53
Bemis, Lynne; Chan, Denise A; Finkielstein, Carla V et al. (2004) Distinct aerobic and hypoxic mechanisms of HIF-alpha regulation by CSN5. Genes Dev 18:739-44