| Project/Area Number |
17390080
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (B)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
General medical chemistry
|
|---|
| Research Institution | Tohoku University |
|---|
Principal Investigator |
IGARASHI Kazuhiko Tohoku University, SCA.,Graduaic School of Medicihe, Prefessor, 大学院医学系研究科, 教授 (00250738)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
MUTO Akihiko Tohoku University, Graduate School of Medicine, Reserch Associate, 大学院医学系研究科, 助手 (80343292)
IKURA Tsuyoshi Tohoku University, Graduate School of Medicine, Lecturer, 大学院医学系研究科, 講師 (70335686)
|
|---|
| Project Period (FY) |
2005 – 2006
|
| Project Status |
Completed (Fiscal Year 2006)
|
| Budget Amount *help |
¥14,500,000 (Direct Cost: ¥14,500,000)
Fiscal Year 2006: ¥5,900,000 (Direct Cost: ¥5,900,000)
Fiscal Year 2005: ¥8,600,000 (Direct Cost: ¥8,600,000)
|
|---|
| Keywords | transcription factor / cellular senescence / oxidative stress / Bach1 / heme / ubiquitin / proteasome / 遺伝子 / ストレス / 蛋白質 / 発現制御 / 免疫学 |
|---|
| Research Abstract |
The transcription repressor Bach1 is a sensor and an effecter of heme that regulates the expression of heme oxygenase-1 and globin genes. Heme binds to Bachl, inhibiting its DNA binding activity and inducing its nuclear export. We found that hemin further induced the degradation of endogenous Bachl in NIH3T3 cells, murine embryonic fibroblasts, and murine erythroleukemia cells. In contrast, succinylacetone, an inhibitor of heme synthesis, caused accumulation of Bachl in murine embryonic fibroblasts, indicating that physiological levels of heme regulated the Bachl turnover. Poly-ubiquitination and rapid degradation of overexpressed Bachl were induced by hemin treatment. HOIL-1, an ubiquitin-protein ligase which recognizes heme-bound, oxidized iron regulatory protein 2, was found to bind with Bachl when both were overexpressed in NIH3T3 cells. HOIL-1 stimulated the poly-ubiquitination of Bachl in a purified in vitro ubiquitination system depending on the intact heme binding motifs of Bachl. Expression of dominant negative HOIL-1 in murine erythroleukemia cells resulted in higher stability of endogenous Bachl, raising the possibility that the heme-regulated degradation involved HOIL-1 in murine erythroleukemia. cells. These results suggest that heme within a cell regulates the poly-ubiquitination and degradation of Bachl.
In addition, we found in this study that Bachl inhibits oxidative stress-induced cellular senescence. Bachl-deficient murine embryonic fibroblasts (MEFs) showed profound cellular senescence in response to oxygen in vitro as compared to wild-type control MEFs. Expression profiling of Bachl-deficient MEFs suggested that overexpression of several genes might be responsible for the oxygen-induced cellular senescence.
|
