Pim-1 kinase activates Cdc25A phosphatase, the transcriptional target of c-Myc

Pim-1 激酶激活 Cdc25A 磷酸酶（c-Myc 的转录靶标）

• 批准号: 11671354
• 负责人: MOCHIZUKI Toshihiro
• 金额: $ 2.18万
• 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 (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11671354/
• 关键词: pim-1; c-myc; cdc25A; apoptosis; アポートシス; 遺伝子治療

The pim-1 oncogene encodes a serine/threonine kinase (Pim-1) involved in the transduction of cytokine-triggered mitogenic signals. Pim-1 is unique in that it closely cooperates with c-Myc not only in oncogenesis but also in apoptosis induction. However, the molecular basis of Pim-1 function remains poorly understood, largely because the downstream effector molecule (s) for Pim-1 kinase has not been identified. Here we provide several lines of evidence that Cdc25A cell cycle phosphatase, a direct transcriptional target for c-Myc, is a substrate for Pim-1 kinase and functions as an effector for Pim-1. We found that Pim-1 physically interacts with Cdc25A both in vitro and in vivo and phosphorylates Cdc25A.We also observed that Pim-1-mediated phosphorylation of Cdc25A increases its phosphatase activity. In addition, wild-type Pim-1, but not kinase-inactive Pim-1, enhanced Cdc25A-mediated cellular transformation and apoptosis. Our results indicate that Cdc25A might be a key molecule that links Pim-1 and c-Myc and also ties Pim-1-mediated mitogenic signals to cell cycle machinery.

pim-1癌基因编码丝氨酸/苏氨酸激酶（Pim-1），其参与丝氨酸触发的促有丝分裂信号的转导。Pim-1的独特之处在于它不仅在肿瘤发生中而且在凋亡诱导中与c-Myc密切合作。然而，Pim-1功能的分子基础仍然知之甚少，主要是因为Pim-1激酶的下游效应分子尚未被鉴定。在这里，我们提供了几条线的证据表明，Cdc 25 A细胞周期磷酸酶，一个直接的转录靶c-Myc，是一个底物的Pim-1激酶和功能作为一个效应器的Pim-1。我们发现Pim-1在体内外均能与Cdc 25 A发生物理相互作用，并使Cdc 25 A磷酸化，同时还观察到Pim-1介导的Cdc 25 A磷酸化可提高其磷酸酶活性。此外，野生型Pim-1，而不是激酶失活的Pim-1，增强Cdc 25 A介导的细胞转化和凋亡。我们的研究结果表明Cdc 25 A可能是连接Pim-1和c-Myc的关键分子，也是Pim-1介导的促有丝分裂信号与细胞周期机制的联系。

项目成果

Chi S, Kitanaka C, Noguchi K, Mochizuki T, Nagashima Y, Shirouzu M, Fujita H, Yoshida M, Chen W, Asai A, Himeno M, Yokoyama S, Kuchino Y: "Oncogenic Ras triggers cell suicide through the activation of a caspase-independent cell death program in human canc

Chi S、Kitanaka C、Noguchi K、Mochizuki T、Nagashima Y、Shirouzu M、Fujita H、Yoshida M、Chen W、Asai A、Himeno M、Yokoyama S、Kuchino Y：“致癌 Ras 通过激活

Chi S,Kitanaka C,Noguchi K,Mochizuki,T,Nagashima Y,Shirouzu M,Fujita H,Yoshida M,Chen W,Asai A,Himeno M,Yokoyama S,Kuchino Y.: "Oncogenic Ras triggers cell suicide through the activation of a caspase-independent cell death program in human cancer cells."O

Chi S,Kitanaka C,Noguchi K,Mochizuki,T,Nagashima Y,Shirouzu M,Fujita H,Yoshida M,Chen W,Asai A,Himeno M,Yokoyama S,Kuchino Y.：“致癌 Ras 通过激活触发细胞自杀

Noguchi K,Kitanaka C,Yamana H,Kokubu A,Mochizuki T,Kuchino Y.: "Regulation of c-Myc through phosphorylation at Ser-62 and Ser-71 by c-Jun N-terminal kinase"J Biol Chem. 274(46). 32580-32587 (1999)

Noguchi K、Kitanaka C、Yamana H、Kokubu A、Mochizuki T、Kuchino Y.：“c-Jun N 末端激酶通过 Ser-62 和 Ser-71 磷酸化调节 c-Myc”J Biol Chem。

Mochizuki T,Kitanaka C,Noguchi K,Muramatsu T,Asai A,Kuchino Y: "Physical and functional interactions between Pim-1 kinase and Cdc25A phosphatase. Implications for the Pim-1-mediated activation of the c-Myc signaling pathway."J Biol Chem. 274(26). 18659-18

Mochizuki T、Kitanaka C、Noguchi K、Muramatsu T、Asai A、Kuchino Y：“Pim-1 激酶和 Cdc25A 磷酸酶之间的物理和功能相互作用。对 Pim-1 介导的 c-Myc 信号通路激活的影响。”

Noguchi K, Kitanaka C, Yamana H, Kokubu A, Mochizuki T, Kuchino Y: "Regulation of c-Myc through phosphorylation at Ser-62 and Ser-71 by c-Jun N-terminal kinase"J Biol Chem.. 274(46). 32580-7 (1999)

Noguchi K、Kitanaka C、Yamana H、Kokubu A、Mochizuki T、Kuchino Y：“c-Jun N 末端激酶通过 Ser-62 和 Ser-71 磷酸化调节 c-Myc”J Biol Chem.. 274（