Grant-in-Aid for Scientific Research (S)
|Allocation Type||Single-year Grants|
Obstetrics and gynecology
|Research Institution||KYUSHU UNIVERCITY|
WAKE Norio Kyushu University, Faculty of Medicine, Professor, 医学研究院, 教授 (50158606)
KOBAYASHI Hiroaki Kyushu University, Hospital, Assistant Professor, 病院・講師 (70260700)
KATO Kiyoko Kyushu University, Medical Institute of Bioregulation, Assistant Professor, 生体防御医学研究所, 講師 (10253527)
SONODA Kenzo Kyushu University, Hospital, Research Associate, 病院・助手 (30294929)
UEOKA Yosuke Kyushu University, Hospital, Research Associate, 病院・助手 (50372743)
平川 俊夫 九州大学, 大学病院, 講師 (20218770)
浅野間 和夫 九州大学, 生体防御医学研究所, 助手 (30380413)
井上 貴史 九州大学, 大学病院, 医員 (70380417)
加藤 秀則 九州大学, 大学病院, 講師 (60214392)
松田 貴雄 九州大学, 大学病院, 助手 (10304825)
有馬 隆博 九州大学, 生体防御医学研究所, 助手 (80253532)
|Project Period (FY)
2002 – 2006
Completed(Fiscal Year 2006)
|Budget Amount *help
¥113,230,000 (Direct Cost : ¥87,100,000、Indirect Cost : ¥26,130,000)
Fiscal Year 2006 : ¥22,360,000 (Direct Cost : ¥17,200,000、Indirect Cost : ¥5,160,000)
Fiscal Year 2005 : ¥22,360,000 (Direct Cost : ¥17,200,000、Indirect Cost : ¥5,160,000)
Fiscal Year 2004 : ¥22,360,000 (Direct Cost : ¥17,200,000、Indirect Cost : ¥5,160,000)
Fiscal Year 2003 : ¥22,360,000 (Direct Cost : ¥17,200,000、Indirect Cost : ¥5,160,000)
Fiscal Year 2002 : ¥23,790,000 (Direct Cost : ¥18,300,000、Indirect Cost : ¥5,490,000)
|Keywords||Molecular targeted Therapy / Cancer / senescence / Erα / MDM2 / p53 / p21 / HDAC inhibitor / proline hydroxylase / NECC1 / 絨毛細胞分化 / エストロゲン受容体α / 分子標的治療 / p21CDKインヒビター / ROS / lq42 / 細胞老化誘導遺伝子 / ERα / 活性型Ras / mdm2 / p53 / CDK結合領域|
A. We have cloned the NECCl gene from human chromosome 4 as a senescence inducing gene in choriocaracinoma cells. We investigated the placental anatomy of NECCl KO (-/-) mouse embryos. In the KO placeuta hypertrophy of giant cell layer and suppression of spongio-trophoblast layer formation were noticeable, respectively. NECCl expression was transiently detected in 8.5-11.5 dpc wild type mouse placenta. NECCl was involved in the negative regulation of differentiation from trophoblast stem cell to giant cell.
B. We have cloned the EGLNl gene that has the potential to induce endometrial cancer cell senescence from lg42 region. EGLNl was a member of prolyl hydroxylase family and regulated HIF1 α protein degradation. Inhibition of HIFl α-mediated signaling by FIH or HIFlsiRNA also induced the cancer cell senescence. Overexpression of EGLNl in endometrial cancer cells was able to induce cell senescence through upregulation of p21 CDK ihibitor.
C. We found the ER α activation by the oncogenic K-Ras mutant. Expression of PR or dominant-negative ER mutant elicited the cancer cell senescence. ER α inactivation resulted in the downregulation of MDM2 followed by p53 activation and subsequent p21 upregulation. We have demonstrated the efficacy of new therapies targetted i)functional inactivation of ER α and ii)suppression of MDM2 protein expression, respectively.
D. We have demonstrated the anti-tumor activity of Sodium Butyrate and Valproic acid that are HDAC inhibitors. Both agents were able to induce cancer cell senescence through p21 upregulation. This effect was independent of p53. Now we are planning the clinical research by using Valproic acid.