Functional analysis of the Bim/DLC complex in apoptosis regulation of hematopoietic progenitors

Bim/DLC复合物在造血祖细胞凋亡调节中的功能分析

• 批准号: 12470205
• 负责人: INABA Toshiya
• 金额: $ 2.69万
• 依托单位: HIROSHIMA UNIVERSITY (2001)Jichi Medical University (2000)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12470205/
• 关键词: Hematopoietic progenitors; Apoptosis; Dynein light chain; Bim; BH3-onIy death activators; Ras; PI3-K; mTOR

In order to clarify the roles of the Bim/Dynein light chain complex in apoptosis regulation system of hematopoietic progenitors, we used murine IL-3-dependent cells such as Baf-3 lymphoid cell line. We identified that two distinct signaling pathways regulate the survival of interleukm-3 (IL-3)-dependent hematopoietic progenitors. One originates from the membrane proximal portion of the cytoplasmic domain of the IL-3 receptor (βc chain), which is shared by IL-3 and granulocyte-macrophage colony-stimulating factor and is involved in the regulation of Bcl-XL through activation of STAT5. The other pathway emanates from the distal region of the βC chain and overlaps with downstream signals from constitutively active Ras proteins. We also showed that the expression of Bim, a member of the BH3-only sub family of cell death activators, is downregulated by IL-3 signaling through either of two major Ras pathways : Raf/mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3-K)/mammalian target of rapamycin (mTOR). Akt/phosphokinase B (PKB) does not appear to play a significant role in this regulatory cascade. Bim downregulation has important implications for cell survival, as enforced expression of this death activator at levels equivalent to those induced by cytokine withdrawal led to apoptosis even in the presence of IL-3. We conclude that Bim is a pivotal molecule in cytokine regulation of hematopoietic cell survival.

为了阐明Bim/动力蛋白轻链复合物在造血祖细胞凋亡调节系统中的作用，我们使用了小鼠IL-3依赖性细胞，例如Baf-3淋巴细胞系。我们发现两种不同的信号通路调节白细胞介素-3（IL-3）依赖性造血祖细胞的存活。一种来源于IL-3受体胞质结构域的膜近端部分（βc链），其由IL-3和粒细胞-巨噬细胞集落刺激因子共享，并通过激活STAT 5参与Bcl-XL的调节。另一条途径来自βC链的远端区域，与组成型活性Ras蛋白的下游信号重叠。我们还表明，Bim的表达，一个成员的BH 3-唯一的细胞死亡激活子亚家族，下调IL-3信号通过两个主要的Ras途径：Raf/丝裂原活化蛋白激酶（MAPK）和磷脂酰肌醇3-激酶（PI 3-K）/哺乳动物雷帕霉素靶（mTOR）。Akt/磷酸激酶B（PKB）似乎在这一调节级联中没有发挥重要作用。Bim下调对细胞存活具有重要意义，因为即使在IL-3存在下，这种死亡激活剂在与细胞因子撤回诱导的水平相当的水平上的强制表达也导致细胞凋亡。我们的结论是Bim是一个关键的分子在造血细胞存活的细胞因子调节。

项目成果

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Toshiya Inaba 基因表达及其调控机制（合作） 小泽惠哉主编：“临床遗传医学指南 - 分子医学方法” Nanzando 312（2000）。

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Akimoto 等人：“促红细胞生成素通过磷脂酰肌醇 3 激酶依赖性途径调节血管平滑肌细胞凋亡。”肾脏国际。

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Dang J., Inukai T., Kurosawa H., Goi K., Inaba T., Lenny N.T., Downing J.R., Stifani S., Look A.T.: "The e2a-hlf oncoprotein activates groucho-related genes and suppresses runx1"Mol. Cell. Biol.. 21. 5935-5945 (2001)

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Shinjyo T., Kuribara R., Inukai T., Hosoi H., Kinoshita T., Miyajima A., Houghton P.J., Look A.T., Ozawa K, Inaba T.: "Downregulation of Bim, a proapoptotic relative of Bcl-2, is a pivotal step in cytokine-initiated survival signaling in murine hematopoie

Shinjyo T.、Kuribarara R.、Inukai T.、Hosoi H.、Kinoshita T.、Miyajima A.、Houghton P.J.、Look A.T.、Ozawa K、Inaba T.：“Bim（Bcl-2 的促凋亡亲戚）的下调，