Functional analysis of intracellular factors involved in the growth, differentiation, and transformation of lymphocytes

参与淋巴细胞生长、分化和转化的细胞内因子的功能分析

• 批准号: 04404034
• 负责人: TANIGUCHI Tadatsugu
• 金额: $ 19.84万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (A)
• 财政年份: 1992
• 资助国家: 日本
• 起止时间: 1992 至 1994
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-04404034/
• 关键词: IRF-1; anti-oncogene; apoptosis; leukemia; MDS; IL-2 signaling; IL-2 receptor; Syk tyrosine kinase; Jak family kinase; IRE-1; Sykチロシンキナーゼ; Jak-ファミリーケロシンキナーゼ; チロシンキナーゼ; インターフェロン; IRF-2; 遺伝子ノックアウトマウス; 誘導型NO合成酵素; 転写因子; IRF; 細胞増殖; 癌化; 5q欠

IRF-1 is a transcription factor that functions in the interferon system. We observed that expression of an activated Ha-ras gene in embryo fibroblasts from IRF-1-deficient mice resulted in their oncogenic transformation, indicating that IRF-1 can function as an anti-oncogene. We also observed that Ha-ras-induced apoptosis did not occur in embryo fibroblasts lacking IRF-1. These results strongly suggest that IRF-1 can determine oncogene-induced cell transformation and death. IRF-1 maps to the chromosomal 5q regon, a region frequently deleted in patients afflicted with leukemia or preleukemic myelodysplastic syndrome (MDS). We have shown previously that IRF-1 is a critically-deleted gene in these "5q syndrome" patients. Recently we discovered the existence of an alternatively-spliced form of the IRF-1 mRNA that encodes a protein lacking DNA-binding and anti-oncogenic activities. We found this abnormally-spliced product, but not the normal IRF-1 mRNA,in approximately 20% of patients affli … More cted with leukemia or MDS.Abnormal splicing may thus represent a new mechanism by which IRF-1 is inactivated, thereby promoting the development of leukemia.We have also found that Syk, a non-receptor-type protein kinase (PTK), associates with the intracellular "serine-rich" region of the interleukin-2 receptor beta chain (IL-2Rbeta) and is activated upon IL-2 stimulation. This "serine-rich" region is essential for induction of the c-myc gene and cell proliferation following IL-2 stimulation. Furthermore, we have found that two recently-identified members of the Jak PTK family, Jak-1 and Jak-3, specifically associate with regions of the IL-2Rbeta and -g chains, respoctively, which are critical for transmission of the IL-2 signal, and are rapidly activated upon IL-2 stimulation. Ectopic expression of Jak-3 in NIH 3T3 fibroblasts, which express functional endogenous IL-2R and Jak-1, conferred upon these cells the ability to respond to IL-2 and thereby progress from the G1 to S phase of the cell cycle. Less

IRF-1是在干扰素系统中起作用的转录因子。我们观察到，在IRF-1缺陷小鼠的胚胎成纤维细胞中，激活的Ha-ras基因的表达导致了它们的致癌转化，这表明IRF-1可以作为抗癌基因发挥作用。我们还观察到ha -ras诱导的细胞凋亡不会发生在缺乏IRF-1的胚胎成纤维细胞中。这些结果强烈提示IRF-1可以决定癌基因诱导的细胞转化和死亡。IRF-1映射到染色体5q区域，该区域在患有白血病或白血病前骨髓增生异常综合征（MDS）的患者中经常缺失。我们之前已经证明，IRF-1在这些“5q综合征”患者中是一个关键缺失的基因。最近，我们发现了IRF-1 mRNA的一种选择性剪接形式，它编码一种缺乏dna结合和抗致癌活性的蛋白质。我们在大约20%的白血病或MDS患者中发现了这种异常剪接产物，而不是正常的IRF-1 mRNA。因此，异常剪接可能代表了IRF-1失活的新机制，从而促进白血病的发展。我们还发现，Syk是一种非受体型蛋白激酶（PTK），与白细胞介素-2受体β链（IL-2Rbeta）的细胞内“富含丝氨酸”区域相关，并在IL-2刺激时被激活。这个“富含丝氨酸”的区域对于诱导c-myc基因和IL-2刺激后的细胞增殖至关重要。此外，我们发现最近发现的两个Jak PTK家族成员，Jak-1和Jak-3，分别与IL-2Rbeta和-g链的区域特异性相关，这些区域对IL-2信号的传递至关重要，并在IL-2刺激时迅速激活。Jak-3在NIH 3T3成纤维细胞中异位表达，表达功能性内源性IL-2R和Jak-1，赋予这些细胞对IL-2作出反应的能力，从而从细胞周期的G1期进展到S期。少

项目成果

Tadatsugu Taniguchi: "The IL-2/IL-2 receptor system:A current overview" Cell. 73. 5-8 (1993)

Tadatsugu Taniguchi：“IL-2/IL-2 受体系统：当前概述”细胞。

Miyazaki, T., Kawahara, A,Fujii, H., Nakagawa, Y., Nminami, Y., Liu, Z-J., Oishi, I., Silvennoinen, O., Witthuhn, B.A., Ihle, J.N., Taniguchi, T.: "Functional activation of Jak 1 and Jak3 by selective association with IL-2 receptor subunits." Science. 266

宫崎，T.，川原，A，藤井，H.，中川，Y.，Nminami，Y.，刘，Z-J.，大石，I.，Silvennoinen，O.，Witthuhn，B.A.，Ihle，J.N.，谷口，T

Nobuyuki Tanaka: "Cellular commitment to oncogene-induced transformatin or apoptosis is dependent on the transcription factor IRF-1." Cell. 77. 829-839 (1994)

Nobuyuki Tanaka：“细胞对癌基因诱导的转化蛋白或细胞凋亡的承诺取决于转录因子 IRF-1。”

Toru Kimura: "Involvemento of the IRF-1 transcription factor in antiviral responses to interferoms" Science. 264. 1921-1924 (1994)

Toru Kimura：“IRF-1 转录因子参与干扰素的抗病毒反应”《科学》。

Kamijo, R., Harada, H., Matsuyama, T., Bosland, M., Gerecitano, J., Shapiro, D., Koh, S.I., Kimura, T., Green, J.S., Mak, T.W., Taniguchi, T., Vilcek, J.: "Essential role for the transcription factor IRF-1 in the induction of nitric oxide synthase in macr

Kamijo, R.、Harada, H.、Matsuyama, T.、Bosland, M.、Gerecitano, J.、Shapiro, D.、Koh, S.I.、Kimura, T.、Green, J.S.、Mak, T.W.、Taniguchi, T