Studies on the function of LKB I /STK II, a Ser/Thr kinase mutated in Peutz-Jeghers syndrome

黑斑息肉综合征中 Ser/Thr 激酶突变 LKB I/STK II 的功能研究

• 批准号: 13470033
• 负责人: AKIYAMA Testu
• 金额: $ 9.34万
• 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 (B)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13470033/
• 关键词: Tumor suppressor; Peutz-Jeghers syndrome; LKB1; STK11; Hamartomatous polyps; Serine-threonine kinase; Peutz-Jeghers症候群; LKB1AP; 好発癌性疾患

Peutz-Jeghers syndrome is an autosomal dominant disease. Early manifestations of Peuts-Jegehers syndrome include melanocytic macules of the lips and multiple hamartomatous polyps in the gastrointestinal tract. Later in life, Peuts-Jeghers syndrome patients have a dramatically increased incidence of cancers in a wide variety of tissues. We investigated the mechanism and function of LKB1/STK11, a Ser/Thr kinase mutated in Peutz-Jehgers syndrome, and made the following findings. 1) We performed a yeast two-hybrid screen using LKB/STK11 as bait, and identified the LMO family of transcription factors as partners for LKB1/STK11. 2) The LMO family of transcription factors interacts with GATA and activates its activity. 3) In cooperation with p53, the LMO family of transcription factors activates the expression of CDK inhibitor p21. Ldb1 and GATA6 were also found to participate in the LMO family-mediated transactivation of p21. 4) Overexpression of LKB1/STK11 in Hela cells as well as in G361 cells resulted in the G1 arrest of the cell cycle. 5) So far we have not succeeded to identify substrate proteins for phosphorylation by LKB1/STK11.

Peutz-Jeghers综合征是一种常染色体显性遗传病。Peuts-Jegehers综合征的早期表现包括嘴唇的黑素细胞斑点和胃肠道的多发错构瘤息肉。在生命的后期，佩茨-杰格斯综合征患者在各种组织中癌症的发病率急剧增加。我们研究了在Peutz-Jehgers综合征中发生突变的丝氨酸/苏氨酸激酶LKB1/STK11的机制和功能，并得出了以下发现。1)以LKB/STK11为诱饵进行酵母双杂交筛选，确定LMO家族转录因子为LKB1/STK11的合作伙伴。2) LMO转录因子家族与GATA相互作用，激活GATA活性。3) LMO家族转录因子与p53共同激活CDK抑制剂p21的表达。Ldb1和GATA6也被发现参与LMO家族介导的p21的转激活。4) Hela细胞和G361细胞中LKB1/STK11过表达导致细胞周期G1阻滞。5)到目前为止，我们还没有成功地鉴定出LKB1/STK11磷酸化的底物蛋白。

项目成果

Y.Kawasaki: "Mutated APC and Asef are Involved in Migration of Colorectal Tumor Cells."Nature Cell Biology. 5・3. 211-215 (2003)

Y. Kawasaki：“突变的 APC 和 Asef 参与结直肠肿瘤细胞的迁移。”《自然细胞生物学》5·3（2003）。

Takemura M.: "Phosphorylation-dependent migration of retinoblastoma protein into the nucleolus triggered by binding to nucleophosmin/B23"Exp. Cell Res.. 276. 233-241 (2002)

Takemura M.：“通过与核磷蛋白/B23结合触发视网膜母细胞瘤蛋白磷酸化依赖性迁移至核仁”Exp。

T.Koyama: "Mutation and Expression of the β-Catenin-interacting Protein ICAT in Human Colorectal Tumors"Jpn. J. Clin. Oncol.. 32(9). 358-362 (2002)

T. Koyama：“人结直肠肿瘤中β-连环蛋白相互作用蛋白ICAT的突变和表达”J. Clin. 32(9) (2002)。

Y. Kawasaki: "Mutated APC and Asef are Involved in Migration of Colorectal Tumor Cells"Nature Cell Biol.. 5 (3). 211-215 (2003)

Y. Kawasaki：“突变的 APC 和 Asef 参与结直肠肿瘤细胞的迁移”Nature Cell Biol.. 5 (3)。

T.Okabe: "RICS, a novel GTPase-Activating Protein for Cdc42 and Rac1, is involved in the b-catenin-N-cadherin and NMDA receptor signaling"J. Biol. Chem.. (in press).

T.Okabe：“RICS 是 Cdc42 和 Rac1 的新型 GTP 酶激活蛋白，参与 b-连环蛋白-N-钙粘蛋白和 NMDA 受体信号传导”J.