Cell cycle transactivation factor E2F-4 is associate with the ganstrointestinal carcinogenesis and/or acquisition of chemoresistance

细胞周期反式激活因子E2F-4与胃肠癌发生和/或化疗耐药性的获得有关

• 批准号: 11671237
• 负责人: TANAKA Noriaki
• 金额: $ 2.3万
• 依托单位: Okayama University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11671237/
• 关键词: colon cancer; genetic instability; E2F-4; chemosensitivity; 大腸癌; 化学療法

E2F is a family of transcription factors implicated in the regulation of gene expression required for progression through the G1-S transition. We have previously detected tumor-specific mutations at a trinucleotide repeat coding sequence of E2F-4 gene in a subset of human sporadic colorectal cancers. The purpose of this study was to investigate the potential functional consequences of these E2F-4 mutations. We transfected NIH3T3 fibroblasts with expression constructs containing wild type as well as mutant E2F-4 cDNA and the effect of the E2F-4 mutations on proliferation was examined. Alteration in transactivation of the E2F consensus promoter sequence was also examined by transient cotransfection of a E2F-4 with a DP-2 construct into cultured human cells. Transfected cell clones overexpressing mutant E2F-4 grew more rapidly and showed higher proliferative activity by increased immunohistochemical staining for proliferating cell nuclear antigen (PCNA). All three mutant forms of E2F-4 showed elevated transactivation of the E2F consensus promoter sequence. Thus, expression of mutant E2F-4s confers a growth advantage in vivo, and this effect may be related to the acquisition of a neoplastic phenotype.

E2 F是一个转录因子家族，参与调控G1-S转换所需的基因表达。我们以前在散发性结直肠癌的一个亚组中检测到E2 F-4基因三核苷酸重复编码序列的肿瘤特异性突变。本研究的目的是调查这些E2 F-4突变的潜在功能后果。我们用含有野生型以及突变型E2 F-4 cDNA的表达构建体转染NIH 3 T3成纤维细胞，并检查E2 F-4突变对增殖的影响。通过将E2 F-4与DP-2构建体瞬时共转染到培养的人细胞中，也检查了E2 F共有启动子序列反式激活的改变。过表达突变体E2 F-4的转染细胞克隆生长更迅速，增殖细胞核抗原（PCNA）的免疫组化染色增加，表现出更高的增殖活性。E2 F-4的所有三种突变形式均显示E2 F共有启动子序列的反式激活升高。因此，突变体E2 F-4s的表达赋予体内生长优势，并且这种效应可能与获得肿瘤表型有关。

项目成果

Matsubara N, et al.: "Role of E2F-4 mutations in chemosensitivy"Proc. Annu. Meet. Am. Assoc. Cancer Res.. 40. A2822 (1999)

Matsubara N 等：“E2F-4 突变在化学敏感性中的作用”Proc。

Matsubara N, et al.: "Multiple tumors and a novel E2F-4 mutation"Digestion. 62. 213-216 (2000)

Matsubara N 等人：“多种肿瘤和新型 E2F-4 突变”消化。

馬場正三他: "21世紀の大腸癌診断治療戦略のために HNPCC in the year2000"株式会社マイライフ社. 71 (2000)

Shozo Baba等：“2000年21世纪HNPCC的结直肠癌诊断和治疗策略” My Life Co., Ltd. 71 (2000)

Matsubara N, et al: "The farthest 3' distal end APC mutation identified in attenuated adenomatous polyposis coli with extracolonic manifestations."Dis.Colon Rectum. 43・5. 720-721 (2000)

Matsubara N 等人：“在具有结肠外表现的减毒腺瘤性息肉病中鉴定出最远的 3 远端 APC 突变。”Dis.Colon Rectum。 720-721 (2000)。

松原長秀 他: "大腸癌の遺伝子変異と臨床応用の可能性."日本外科学会雑誌. 101・6. 468-475 (2000)

Nagahide Matsubara 等：“结直肠癌的基因突变及其临床应用的可能性。”日本外科学会杂志 101・6（2000 年）。