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

我们通过对细胞生长调控的研究，特别是对蛋白质磷酸化的兴趣，展示了以下几点。1.ToB(1)ToB具有肿瘤抑制作用，因为#1：ToB在过度表达时会抑制细胞生长，#2：ToB缺陷小鼠易患癌症，#3：ToB在各种人类肿瘤中的表达通常被抑制。(2)在生长因子刺激下，Tob被ERK1/2磷酸化，导致Tob的抗增殖活性丧失。(3)ToB参与转录调控是因为#1：ToB与HDAC结合，抑制细胞周期蛋白基因的转录，#2：ToB通过与Smads相互作用调节BMP信号。因此，TOB缺陷小鼠形成了一种骨化表型。#3：ToB与至少由10个CNOT蛋白(Cnot1-10)组成的NOT转录机制的复合体。在cnot蛋白中，cnot7与rxrβ相互作用，与rxrβ缺陷小鼠一样，cnot7缺陷小鼠由于…寡核苷酸而不育。更多的无畸形精子症。(4)ToB穿梭于胞核和胞质之间。在细胞质中，Tob与Polya结合蛋白结合，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)制备的激动型单抗可激活PC12细胞表面的受体酪氨酸激酶ALK，诱导其增殖和神经分化。(3)ALK利用SNT2接头蛋白进行细胞信号转导，这与激活的ALK对恶性细胞的转化有关。3.M期蛋白激酶(1)果蝇肿瘤抑制蛋白LATS1/2人同源物的过表达导致M期细胞停滞。(2)RNAi下调LATS2相互作用蛋白Ajuba可抑制纺锤体的形成和染色体分离。(3)Ajuba还通过与β-catenin的相互作用负性调节Wnt信号。(4)Cdc2对染色质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。较少

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