| Project/Area Number |
17390090
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (B)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Pathological medical chemistry
|
|---|
| Research Institution | Kanazawa University |
|---|
Principal Investigator |
SATO Hiroshi Kanazawa University, Cancer Research Institute, Professor, がん研究所, 教授 (00115239)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
TAKAHISA Takino Kanazawa University, Cancer Research Institute, Associate Professor, がん研究所, 助教授 (40322119)
MIYAMORI Hisashi Kanazawa University, Cancer Research Institute, Research Associate, がん研究所, 助手 (30345631)
|
|---|
| Project Period (FY) |
2005 – 2006
|
| Project Status |
Completed (Fiscal Year 2006)
|
| Budget Amount *help |
¥14,300,000 (Direct Cost: ¥14,300,000)
Fiscal Year 2006: ¥6,000,000 (Direct Cost: ¥6,000,000)
Fiscal Year 2005: ¥8,300,000 (Direct Cost: ¥8,300,000)
|
|---|
| Keywords | MT1-MMP / Apolipoprotein E / inflammatory diseases / Cancer / APP / alpha secretase / GDF15 / p53 / ベーターアミロイド / TGFベーター / 増殖抑制 / MT-MMP / 癌 / セレクターゼ / Fe65 / 転写活性化 |
|---|
| Research Abstract |
Membrane-type matrix metalloproteinase-1 (MT1-MMP) is closely associated with tumor, inflammatory diseases and so on. To explore the function of MT1-MMP in these diseases, we developed expression cloning strategy to identify novel substrates for it, and identified following substrates.
1. Apolipoprotein E (ApoE) is involved in not only lipoprotein clearance but also cell regulatory functions that prevent vascular disease. We identified ApoE as a substrate for MT1-MMP. Cleavage of ApoE by MT1-MMP may abrogate suppression of growth and migration of smooth muscle cells by ApoE, and contribute to the stimulation of tissue remodeling.
2. Amyloid precursor protein (APP) was shown to be cleaved by MT1-MMP and brain-specific MT3-MMP and MT5-MMP within a beta peptide sequence, and the cytoplasmid domain was shed into culture medium. Although these MT-MMPs are alpha secretases, synthesis of beta amyloid peptide was not reduced by them. These results suggest that beta amyloid peptide may not be generated on cell surface.
3. MT1-MMP was shown to cleave the mature form of a TGF beta family member GDF15/MIC-1 at Asn252-Met253 peptide bond and inactivate cytokine activity. GDF15 suppressed tumor cell growth by inducing phosphorylation of p53 and synthesis of p21. Thus, cleavage of GDF15 by MT1-MMP abrogated growth suppression of tumor cells. These results suggested that combination therapy of GDF15 and MMP inhibitor may have potent growth inhibitory effect on tumor cells.
|
