Regulation of cell-cycle movement and cell transformation by c-Myc and its binding proteins

c-Myc 及其结合蛋白对细胞周期运动和细胞转化的调节

• 批准号: 12470490
• 负责人: ARIGA Hiroyoshi
• 金额: $ 6.66万
• 依托单位: HOKKAIDO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12470490/
• 关键词: c-Myc; oncogene; tumor suppressor; transformation; transcription factor; co-repressor; embryonic lethal; spermatogenesis; c-myc; co-repressor; 転写制御; 細胞周期; タンパク質分解; リン酸化; クロマチン

1).MM-1MM-1 was found to have an mutation of alanine (A) at amino acid number 157 to arginine (R) in a high frequency of the patients of leukemia, lymphoma and scc-type of tongue cancers. This mutation of MM-1 abrogates all the functions of MM-1 to c-Myc, including repression of activities for transcription, cell transformation, and cell growth. The transrepression pathway of MM-1 to c-Myc was found to be carried out by the recruitment of HDAC complex by TIF1b that MM-1 binds. Furthermore, we have found that MM-1 also stimulates the degradation of c-Myc in a ubiquitin-independent manner and that this activity of A157R mutation of MM-1 was hampered. We also identified the splicing isoforms of MM-1 by an alternative splicing of the gene mapped to chromosome 12 and each isoform was found to be distinctly located in cells.2).AMY-1AMY-1 was found to bind to WAVE1 to relocalize the site for actin polymerization and also to AKAP84, an anchoring protein of A-kinase, for participating in the spermatogenesis.3). MSSPDisruption of mssp gene in mice showed some embryonic lethality, indication that MSSP functions in early embryogenesis.

MM-1 MM-1在白血病、淋巴瘤和SCC型舌癌患者中发现高频率的第157位氨基酸的丙氨酸（A）突变为精氨酸（R）。MM-1的这种突变消除了MM-1到c-Myc的所有功能，包括抑制转录、细胞转化和细胞生长的活性。发现MM-1到c-Myc的反式阻遏途径是通过MM-1结合的TIF 1b募集HDAC复合物来进行的。此外，我们发现MM-1还以不依赖于泛素的方式刺激c-Myc的降解，并且MM-1的A157 R突变的这种活性受到阻碍。我们还通过选择性剪接定位于12号染色体的基因鉴定了MM-1的剪接异构体，发现每种异构体在细胞中的位置不同。2）AMY-1AMY-1被发现与WAVE 1结合以重新定位肌动蛋白聚合位点，也与AKAP 84结合，AKAP 84是A-激酶的锚定蛋白，参与精子发生。MSSP在小鼠中破坏mssp基因显示出一定的胚胎致死性，表明MSSP在早期胚胎发生中起作用。

项目成果

Koike, N.: "Identification of heterochromatin protein 1 (HP1) as a phosphorylation target by Pim-1 kinase and the effect of phosphorylation on the transcriptional repression function of HP1."FEBS Letters. 475. 17-21 (2000)

Koike, N.：“异染色质蛋白 1 (HP1) 作为 Pim-1 激酶磷酸化靶标的鉴定以及磷酸化对 HP1 转录抑制功能的影响。”FEBS Letters。

Takahashi, K.: "DJ-1 positively regulates the androgen receptor by impairing the binding of PIASxα to the receptor"J. Biol. Chem.. 276. 37556-37563 (2001)

Takahashi, K.：“DJ-1 通过损害 PIASxα 与受体的结合来正向调节雄激素受体”J. Biol. 276. 37556-37563 (2001)

Takahashi, K.,et al.: "DJ-1 positively regulates the androgen receptor by impairing the binding of PIASx α to the receptor"J. Biol. Chem.. 276. 37556-3756 (2001)

Takahashi, K., et al.：“DJ-1 通过削弱 PIASx α 与受体的结合来正向调节雄激素受体”J. Biol. 276. 37556-3756 (2001)

Fujimoto, M.: "Disruption of MSSP, c-myc single-strand binding protein, leads to embryonic lethality in some homozygous mice"Genes Cells. 6. 1067-1075 (2001)

Fujimoto, M.：“MSSP（c-myc 单链结合蛋白）的破坏会导致一些纯合小鼠的胚胎致死”Genes Cells。

Ono, T.: "TOK-1, a novel p21 Cip1-binding protein that cooperatively enhances p21- dependent inhibitory activity toward CDK2 kinase."J.Biol.Chem.. 275. 31145-31154 (2000)

Ono, T.：“TOK-1，一种新型 p21 Cip1 结合蛋白，可协同增强对 CDK2 激酶的 p21 依赖性抑制活性。”J.Biol.Chem.. 275. 31145-31154 (2000)