| Project/Area Number |
11470484
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (B)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Biological pharmacy
|
|---|
| Research Institution | THE UNIVERSITY OF TOKYO |
|---|
Principal Investigator |
SATO Ryuichiro Graduate School of Agricultural and Life Sciences, THE UNVERSITY OF TOKYO, Associate Professor, 大学院・農学生命科学研究科, 助教授 (50187259)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
DOI Takefumi Osaka University, Graduate School of Pharmaceutical Sciences, Professor, 大学院・薬学研究科, 教授 (00211409)
|
|---|
| Project Period (FY) |
1999 – 2001
|
| Project Status |
Completed (Fiscal Year 2001)
|
| Budget Amount *help |
¥14,400,000 (Direct Cost: ¥14,400,000)
Fiscal Year 2001: ¥4,200,000 (Direct Cost: ¥4,200,000)
Fiscal Year 2000: ¥4,900,000 (Direct Cost: ¥4,900,000)
Fiscal Year 1999: ¥5,300,000 (Direct Cost: ¥5,300,000)
|
|---|
| Keywords | SREBP / Proteasome / Uboiquitination / 転写因子 / コレステロール / 転写調節 / 分解 |
|---|
| Research Abstract |
Sterol regulatory element-binding proteins (SREBPs) are synthesized as membrane-bound precursors and processed to generate transcriptionally active forms. The active SREBPs translocate to the nucleus, induce the expression of responsive genes and are degraded very rapidly. Treatment with proteasome inhibitors elevates the amount of the endogenous nuclear SREBPs, but not the precursors, in HeLa cells. Nuclear forms of human SREBP-la (amino acids 1-487) and SREBP-2 (amino acids 1-481), which are transiently expressed in stable Chinese hamster ovary cell lines (CHO-487 and -481), are also stabilized by proteasome inhibitors, suggesting that the nuclear SREBPs are likely to be substrates for the proteasome-dependent proteolysis. The stabilized nuclear SREBPs actively induce the expression of responsive genes including HMG CoA synthase, fatty acid synthase and the low density lipoprotein receptor. The rapid turnover of nuclear SREBP-la is not affected by the intracellular sterol levels and the half-life is estimated to be approximately 3 h. The nuclear SREBPs are found conjugated with a polyubiquitin chain. When this conjugation is inhibited by overexpression of mutant ubiquitin, defective in polyubiquitination, the nuclear SREBPs are partly stabilized and induce the expression of the responsive gene, suggesting that the ubiquitin conjugated-SREBPs are substrates for the proteasome. Taken together, these results demonstrate that the ubiquitin-proteasome system degrades SREBPs and that this system controls the expression of SREBP-responsive genes.
|
