Study of CDK inhibitors in B cell immune response

CDK抑制剂在B细胞免疫反应中的研究

• 批准号: 09044292
• 负责人: TSUBATA Takeshi
• 金额: $ 3.65万
• 依托单位: Medical Research Intitute, Tokyo Medical and Dental University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for international Scientific Research
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09044292/
• 关键词: B lymphocyte; cell death; CDK inhibitor; p27; antigen receptor; c-Myc; Lyn; cell cycle; CDK; 誘導的発現; 増殖; p21; Cdkインヒビター

B lymphocytes undergo apoptosis by strong antigen receptor (BCR) crosslinking. However, CD4O signaling or CD72 ligation abrogates BCR-mediated apoptosis and induces proliferation of BCR-ligated B cells. In the B cell line WEHI-231, BCR ligation increased the level of the CDK inhibitor p27. Inducible expression of CDK inhibitors caused cell death of WEHI-231, suggesting that CDK inhibitors are involved in BCR-mediated apoptosis. In contrast, fibroblasts undergo cell cycle arrest but not apoptosis upon stimulation up-regulating CDK inhibitors. However, those stimulations induce apoptosis in-fibroblasts overexpressing c-Myc. Previously, constitutive overexpression of c-Myc was shown to block BCR-mediated apoptosis in WEHI-231. By inducibly expressing c-Myc, we showed that the previous result is an artifact and that overexpression of c-Myc enhances BCR-mediated apoptosis. Those results strongly suggest that CDK inhibitors and c-Myc play an important role in the regulation of death as well as proliferation of B cells.When B cells survive and proliferate in the presence of CD4O signaling or CD72 ligation, the level of the CDK inhibitor p27 is reduced. We showed that CD72 is phosphorylated by Lyn and negatively regulates BCR signaling by recruiting SHP-1. Moreover, Lyn reduced the expression level of c-Myc. CD72 may thus negatively regulate c-Myc and CDK inhibitors, resulting in survival and proliferation of B cells.

B 淋巴细胞通过强抗原受体 (BCR) 交联而发生凋亡。然而，CD4O 信号传导或 CD72 连接会消除 BCR 介导的细胞凋亡并诱导 BCR 连接的 B 细胞增殖。在 B 细胞系 WEHI-231 中，BCR 连接增加了 CDK 抑制剂 p27 的水平。 CDK 抑制剂的诱导表达导致 WEHI-231 细胞死亡，表明 CDK 抑制剂参与 BCR 介导的细胞凋亡。相反，成纤维细胞在刺激上调 CDK 抑制剂后会经历细胞周期停滞，但不会发生细胞凋亡。然而，这些刺激会诱导过度表达 c-Myc 的成纤维细胞凋亡。此前，c-Myc 的组成型过表达被证明可以阻断 WEHI-231 中 BCR 介导的细胞凋亡。通过诱导表达 c-Myc，我们表明先前的结果是人为因素，c-Myc 的过度表达会增强 BCR 介导的细胞凋亡。这些结果强烈表明CDK抑制剂和c-Myc在B细胞死亡和增殖的调节中发挥重要作用。当B细胞在CD4O信号传导或CD72连接存在的情况下存活和增殖时，CDK抑制剂的水平p27 减少。我们发现 CD72 被 Lyn 磷酸化，并通过招募 SHP-1 负向调节 BCR 信号传导。此外，Lyn 降低了 c-Myc 的表达水平。因此，CD72 可能负向调节 c-Myc 和 CDK 抑制剂，从而导致 B 细胞的存活和增殖。

项目成果

GOITSUKA,R.: "BASH,a novel signaling molecule preferentially expressed in B cells of the bursa of Fabricius." J.Immunol.161・11. 5804-5808 (1998)

GOITSUKA, R.：“BASH，一种优先在法氏囊 B 细胞中表达的新型信号分子。”J.Immunol.161·11 (1998)。

SUZUKI Y.: "HAX-1, a novel intracellular protein, localized on mitochondria, directly associates with HS1, a substrate of Src family tyrosine kinases." J.Immunol.158・6. 2736-2744 (1997)

SUZUKI Y.：“HAX-1 是一种位于线粒体上的新型细胞内蛋白，与 Src 家族酪氨酸激酶的底物 HS1 直接相关。J.Immunol.158・6 (1997)。

Adachi, T.: "The B cell surface protein CD72 recruits the tyrosine phosphatase SHP-1 upon tyrosine phosphorylation." J. Immunol.160. 4662-4665 (1998)

Adachi, T.：“B 细胞表面蛋白 CD72 在酪氨酸磷酸化后招募酪氨酸磷酸酶 SHP-1。”

Suzuki Y.: "HAX-1, a novel intracellular protein, localized on mitochondria, directly associates with HSI, a substrate of Src family tyrosine kinases." J.Immunol.158. 2736-2744 (1997)

Suzuki Y.：“HAX-1 是一种新型细胞内蛋白，位于线粒体上，与 Src 家族酪氨酸激酶的底物 HSI 直接相关。”

Hagiyama,H.: "Signaling through the antigen receptor of B lymphocytes activates a pathway independent of p53-mediated transactivation for c-Myc-induced apoptosis." Oncogene.(in press).

Hagiyama, H.：“通过 B 淋巴细胞抗原受体发出的信号激活一条独立于 p53 介导的反式激活的通路，从而导致 c-Myc 诱导的细胞凋亡。”