| Project/Area Number |
14370302
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (B)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Hematology
|
|---|
| Research Institution | Osaka University |
|---|
Principal Investigator |
KANAKURA Yuzuru Osaka University, Graduate School of Medicine, Professor, 医学系研究科, 教授 (20177489)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
SHIBAYAMA Hirohiko Osaka University, Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (60346202)
MIZUKI Masao Osaka University, Graduate School of Medicine, Lecturer, 医学系研究科, 講師 (80283761)
MATSUMURA Itaru Osaka University, Graduate School of Medicine, Associate Professor, 医学系研究科, 助教授 (00294083)
SUGAHARA Hiroyuki Osaka University, Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (40362701)
|
|---|
| Project Period (FY) |
2002 – 2003
|
| Project Status |
Completed (Fiscal Year 2003)
|
| Budget Amount *help |
¥15,000,000 (Direct Cost: ¥15,000,000)
Fiscal Year 2003: ¥5,400,000 (Direct Cost: ¥5,400,000)
Fiscal Year 2002: ¥9,600,000 (Direct Cost: ¥9,600,000)
|
|---|
| Keywords | KIT / FLT3 / ROS / E2F1 / NF-kB / apoptosis / Anamorsin / Bcl-XL / NF-κB / PML / 増殖 / 分化 / シグナル伝達 / STAT3 / 転写因子 / 白血病 / RARα |
|---|
| Research Abstract |
In this study, we have analyzed the mechanisms of growth, differentiation and malignant transformation of hematopoietic cells from the aspects of signal transduction, transcriptional regulation, cell cycle regulation and apoptosis and got the results as follows :
1.Both wild-type KIT and oncogenic (Asp814Val) KIT induce cell growth by activating PI3-K signal pathway through Tyrosine719.
2.Wild type KIT mediates chemotaxis by activating Src family tyrosine kinases and PI3-K through Tyrosine719 and Tyrosine567.
3.Oncogenic FLT3 containing the internal tandem duplication (ITD) enhances the expression of Pim-2 that mediates cell growth, while it suppresses that of PU.1 and c/EBPa, both of which induce granulocytic differentiation, thereby enhancing the growth and inhibiting the differentiation of immature myeloid cells.
4.Functional cooperation among Ras, STAT5, and PI3-K is required for full oncogenic activity of BCR/ABL oncogene.
5.PML inhibits STAT3 activity, while its oncogenic form PML/RARa enhances its activity.
6.E2F1, a critical regulator of Gl/S transition, sensitizes host cells to apoptosis by inhibiting NF-kB activity specifically at Gl/S transition.
7.We have cloned a novel anti-apoptotic molecule Anamorsin, which reveals no homology to known apoptosis related molecules.
8.Knockout mice for Anamorsin are embryonic lethal at late gestation due to the defect of definitive hematopoiesis.
|
