Mechanisms of cell growth and malignant transformation regulated by protein phosphorylation and dephosphorylation

蛋白质磷酸化和去磷酸化调控细胞生长和恶性转化的机制

• 批准号: 12219201
• 负责人: YAMAMOTO Tadashi
• 金额: $ 149.57万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research on Priority Areas
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12219201/
• 关键词: cancer; cell growth; signal transduction-; tumor suppressor gene; protein phosphorylation; transcription factor complex; gene manipulated mice; RNAi; 蛋白質; 転写複合体; プロテオーム; 蛋白質リン酸化反応; 細胞周期; 肺癌細胞株; 遺伝子欠損マウス; Tob; Caf1; CCR4; NOT; LATS; Ndr

We showed the followings through the studies on cell growth regulation with special interest in protein phosphorylation. 1. Tob (1) Tob functions as a tumor suppressor because #1: tob suppresses cell growth when overexpressed, #2: tob-deficient mice are prone to cancer, and #3: expression of tob mRNA is often suppressed in various human tumors. (2) Tob becomes phosphorylated by Erk1/2 upon growth factor stimulation, which results in the loss of anti-proliferative activity of Tob. (3) Tob participates in transcription regulation because #1: Tob associate with HDAC and suppresses transcription of the cyclin Dl gene, #2: Tob regulates BMP signaling through its interaction with Smads. Consequently, tob-deficient mice develop an osteopetrotic phenotype. #3: Tob complexes with the NOT transcription machinery that consists of at least 10 Cnot proteins (Cnot1-10). Among Cnot proteins Cnot7 interacts with RXRβ, and like RXRβ-deficient mice Cnot7-deficient mice are sterile because of Oligo-asthe … More no-teratozoospermia. (4) Tob shuttles between nucleus and cytoplasm. In the cytoplasm Tob associates with polyA binding protein and regulates translation of mRNA. 2. Tyosine phosphorylation (1) Cbl-c induces v-Src ubiquitination and degradation, and thereby suppresses v-Src-mediated malignant transformation. (2) Agonistic monoclonal antibody we produced activates receptor tyrosine kinase ALK on the surface of PC12 cells, and induces their proliferation and neuronal differentiation. (3) ALK utilizes SNT2 adaptor protein for cell signaling, which is relevant to malignant cell transformation by activated ALK. 3. M phase kinases (1) Overexpression of human homologs of drosophila tumor suppressor proteins LATS1/2 results in M phase arrest. (2) RNAi-mediated down-regulation of LATS2-interacting protein Ajuba induces inhibition of spindle formation and chromosome segregation. (3) Ajuba also negatively regulates Wnt signaling through its interaction with β-catenin. (4) Phosphorylation of chromokinesin Kid by Cdc2 is important for chromosome dynamics and M phase progression. These data contributes to deepening our understanding on cell growth regulation. Less

我们通过对细胞生长调控的研究，特别是对蛋白磷酸化的研究，表明了以下几点。1. Tob（1）Tob作为肿瘤抑制因子发挥作用，因为#1：tob在过度表达时抑制细胞生长，#2：tab缺陷小鼠容易患癌症，#3：tob mRNA的表达通常在各种人类肿瘤中受到抑制。(2)Tob在生长因子刺激后被Erk 1/2磷酸化，这导致Tob的抗增殖活性丧失。(3)Tob参与转录调节，因为#1：Tob与HDAC结合并抑制细胞周期蛋白Dl基因的转录，#2：Tob通过其与Smads的相互作用调节BMP信号传导。因此，β 2-缺陷小鼠发展成骨硬化表型。#3：Tob与至少由10个Cnot蛋白（Cnot 1 -10）组成的NOT转录机制复合。在Cnot蛋白中，Cnot 7与RXRβ相互作用，并且与RXRβ缺陷小鼠一样，Cnot 7缺陷小鼠由于寡聚天冬氨酸而不育。 ...更多信息 无畸形精子症(4)托布穿梭于细胞核和细胞质之间。在细胞质中，Tob与polyA结合蛋白结合并调节mRNA的翻译。2.酪氨酸磷酸化（1）Cbl-c诱导v-Src泛素化和降解，从而抑制v-Src介导的恶性转化。(2)我们制备的激动性单克隆抗体可激活PC 12细胞表面的受体酪氨酸激酶ALK，并诱导其增殖和神经元分化。(3)ALK利用SNT 2衔接蛋白进行细胞信号传导，这与活化ALK引起的恶性细胞转化有关。3. M期激酶（1）果蝇肿瘤抑制蛋白LATS 1/2的人类同源物的过表达导致M期阻滞。(2)RNAi介导的LATS 2相互作用蛋白Ajuba的下调诱导纺锤体形成和染色体分离的抑制(3)Ajuba还通过与β-catenin的相互作用负调节Wnt信号传导。(4)Cdc 2对Kid的磷酸化对染色体动力学和M期进程具有重要意义。这些数据有助于加深我们对细胞生长调控的理解。少

项目成果

Association of ANA, a member of the antiproliferative Tob family proteins, with a Caf1 component of the CCR4 transcriptional regulatory complex.

• DOI: 10.1111/j.1349-7006.2001.tb01135.x
• 发表时间: 2001-06
• 期刊: Japanese journal of cancer research : Gann
• 作者: Yoshida Y;Hosoda E;Nakamura T;Yamamoto T
• 通讯作者: Yamamoto T

Role of the rasGAP-associated docking protein p62(dok) in negative regulation of B cell receptor-mediated signaling.

• DOI: 10.1101/gad.14.1.11
• 发表时间: 2000-01
• 期刊: Genes & development
• 影响因子: 10.5
• 作者: Y. Yamanashi;T. Tamura;Toshihide Kanamori;H. Yamane;H. Nariuchi;Tadashi Yamamoto;D. Baltimore

A role of FAK in the concanavalin A-dependent secretion of matrix metalloproteinase-2 and-9

FAK 在基质金属蛋白酶 2 和 9 的伴刀豆球蛋白 A 依赖性分泌中的作用

• 发表时间: 2000
• 期刊: Oncogene 19
• 作者: Takaku;K et al.;T.T.Sein
• 通讯作者: T.T.Sein

Kuo ML et al.: "Arf induces p53-dependent and independent anti-proliferative genes"Cancer Res. 63. 1046-1053 (2003)

Kuo ML 等人：“Arf 诱导 p53 依赖性和独立的抗增殖基因”Cancer Res。

Aurine Tricarboxylic Acid, a potent metal-chelating inhibitor of NF κB-DNA binding.

金三羧酸，一种有效的 NF κB-DNA 结合金属螯合抑制剂。

• 发表时间: 2000
• 期刊: Bioorg Med. Chem. 8
• 作者: K.M.Sharma