Signal transduction in cell division

细胞分裂中的信号转导

• 批准号: 15570154
• 负责人: SHIRAKATA Masaki
• 金额: $ 2.05万
• 依托单位: Tokyo Medical and Dental University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15570154/
• 关键词: Cell cycle reguration; Cell growth; Cancer; Apoptosis; シグナル伝達; 細胞周期; ゲノム複製; EBウイルス; MAPK

Dok-1 and Dok-2 are rasGAP-associated adaptor proteins expressed preferentially in hematopoietic cells. We found that Dok-1 plays an important role of cell cycle progression in cultured cells. We also generated mice lacking Dok-1 and/or Dok-2 ; among them, the double-deficient mice succumbed to myeloproliferative disease resembling human chronic myelogenous leukemia (CML) and chronic myelomonocytic leukemia. The double-deficient mice had increased hematpoietic stem cells and displayed medullary and extramedullary hyperplasia of granulocyte/macrophage progenitors with leukemic potential, and their myeloid cells showed hyper-proliferation and hypo-apoptosis together with enhanced Erk and Akt activation upon cytokine stimulation. Moreover, loss of Dok-1 and/or Dok-2 induced blastic transformation of chronic phase CML-like disease in mice carrying bcr-ab1 gene. These findings demonstrate that Dok-1 and Dok-2 are key negative regulators of cytokine responses and are essential for myeloid homeostasis and suppression of leukemia.

Dok-1和Dok-2是优先在造血细胞中表达的rasGAP相关衔接蛋白。我们发现Dok-1在培养细胞的细胞周期进程中起重要作用。我们还产生了缺乏Dok-1和/或Dok-2的小鼠;其中，双缺陷小鼠死于骨髓增生性疾病，类似于人类慢性粒细胞白血病（CML）和慢性粒单核细胞白血病。双缺陷小鼠具有增加的造血干细胞，并显示具有白血病潜能的粒细胞/巨噬细胞祖细胞的髓内和髓外增生，并且它们的骨髓细胞显示过度增殖和低凋亡，以及在细胞因子刺激后增强的Erk和Akt活化。此外，Dok-1和/或Dok-2的缺失诱导携带bcr-ab 1基因的小鼠发生慢性期CML样疾病的急变。这些发现表明，Dok-1和Dok-2是细胞因子应答的关键负调节因子，并且对于骨髓稳态和抑制白血病是必需的。

项目成果

白形正樹: "Placental extravillous cytotrophoblasts persistently express class I major histocompatibility complex molecules after human cytomegalovirus infection"Journal of Virology. 77. 8187-8195 (2003)

Masaki Shirakata：“人巨细胞病毒感染后胎盘绒毛外细胞滋养层持续表达 I 类主要组织相容性复合体分子”病毒学杂志 77. 8187-8195 (2003)。

CD40 ligand is a critical effector of Epstein-Barr virus in host cell survival and transformation

• DOI: 10.1073/pnas.1231363100
• 发表时间: 2003-06-24
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Imadome, KI;Shirakata, M;Yamanashi, Y
• 通讯作者: Yamanashi, Y

Placental extravillous cytotrophoblasts persistently express class I MHC molecules after human cytomegalovirus infection.

人巨细胞病毒感染后，胎盘绒毛外细胞滋养层持续表达 I 类 MHC 分子。

• 发表时间: 2003
• 期刊: Journal of Virology 77
• 作者: Niimi;N.;白形 正樹
• 通讯作者: 白形 正樹

白形正樹: "CD40 ligand is a critical effector of Epstein-Barr virus in host cell survival and transformation"Proceedings of Ntional Academy of Sciences USA. 100. 7836-7840 (2003)

Masaki Shirakata：“CD40 配体是 Epstein-Barr 病毒在宿主细胞存活和转化中的关键效应物”美国国家科学院院刊 100. 7836-7840 (2003)。

Role of Dok-1 and Dok-2 in myeloid homeostasis and suppression of leukemia.

• DOI: 10.1084/jem.20041247
• 发表时间: 2004-12-20
• 期刊: The Journal of experimental medicine
• 作者: Yasuda T;Shirakata M;Iwama A;Ishii A;Ebihara Y;Osawa M;Honda K;Shinohara H;Sudo K;Tsuji K;Nakauchi H;Iwakura Y;Hirai H;Oda H;Yamamoto T;Yamanashi Y
• 通讯作者: Yamanashi Y