权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

The collapse of the mechanisms which stably maintain M phase chromosome and its biological effect

M期染色体稳定维持机制的崩溃及其生物学效应

基本信息

批准号：
19310034
负责人：
YAMAMOTO Kazuo
金额：
$ 13.31万
依托单位：
Tohoku University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2007
资助国家：
日本
起止时间：
2007 至 2009
项目状态：
已结题

项目摘要

Ortho-phenyl phenol (OPP) and its hepatic metabolite, phenyl hydroquinone (PHQ), are broad-spectrum fungicides and antibacterial agents. OPP and PHQ tested negative in an Ames system and positive with respect to the formation of tumors in the urinary bladder in rats when administered in diet, showing attributes of a non-genotoxic carcinogen. It has also been demonstrated that OPP and PHQ do not bind or cleave DNA in vivo or in vitro, rather dose-dependent protein binding in OPP-treated rats was observed. OPP and PHQ, however, generate chromosomal aberrations including aneuploidy. Thus, the steps by which non-genotoxic carcinogens exert their effects need to be elucidated. In this study, we used an assay of loss of heterozygosity (LOH) in Saccharomyces cerevisiae and cultured human cells to determine the biological effects of OPP and PHQ. LOH was found to be induced by OPP and PHQ because of a functional chromosome loss : aneuploidy. PHQ bound to and interfered with the depolymerization of tubulin in vitro. We further demonstrate that PHQ can arrest the cell cycle at the G2/M transition as a result of the stabilization of Swe1 (Wee1 homolog), probably leading to inactivation of the Cdc28 (Cdk1/Cdc2 homolog). Furthermore, Hog1 (p38 MAPK homolog) was robustly phosphorylated by PHQ, which can stabilize Swe1. On the other hand, Chk1 and Rad53 were not phosphorylated by PHQ, indicating that Mec1/Tel1 DNA damage checkpoint was not functional. Mutation of swe1 and hog1 abolished the PHQ-induced arrest at the G2/M transition and became resistant to PHQ lethality and aneuploidy formation. These results suggest that PHQ-induced G2/M transition checkpoint which is activated by the Hog1-Swe1 pathway plays a role in the formation of aneuploidy. We argue that OPP and PHQ activate MAPK pathway arrested cell cycle at G2/M transition and caused aneuploidy.

邻苯基苯酚（Pho）及其肝脏代谢产物苯基对苯二酚（PHQ）是广谱杀菌剂和抗菌剂。在艾姆斯系统中，当在饮食中给药时，在大鼠膀胱肿瘤形成方面，试验结果为阴性，显示出非遗传毒性致癌物的属性。也已经证明，在体内或体外，OPP和PHQ不结合或切割DNA，而在OPP处理的大鼠中观察到剂量依赖性蛋白结合。然而，PHQ和PHQ产生染色体畸变，包括非整倍性。因此，需要阐明非遗传毒性致癌物发挥其作用的步骤。在这项研究中，我们使用的杂合性缺失（洛）在酿酒酵母和培养的人类细胞的测定，以确定的生物学效应的抑制剂和PHQ。洛缺失被发现是由于非整倍体的功能性染色体丢失引起的。PHQ在体外可与微管蛋白结合并干扰微管蛋白的解聚。我们进一步证明，PHQ可以阻止细胞周期在G2/M转换的结果，稳定的Swe 1（Wee 1同系物），可能导致失活的Cdc 28（Cdk 1/Cdc 2同系物）。此外，Hog 1（p38 MAPK同源物）被PHQ强烈磷酸化，这可以稳定Swe 1。另一方面，Chk 1和Rad 53不被PHQ磷酸化，表明Mec 1/Tel 1 DNA损伤检查点不起作用。swe 1和hog 1的突变废除了PHQ诱导的停滞在G2/M过渡，并成为抵抗PHQ致死性和非整倍体形成。这些结果表明，PHQ诱导的G2/M转换检查点，这是由Hog 1-Swe 1途径激活发挥作用，在非整倍体的形成。我们认为，PHQ和BMPK激活MAPK通路，使细胞周期阻滞在G2/M期，导致细胞非整倍体。

项目成果

期刊论文数量（0）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Benzene metabolite, hydroquinone induces Hog1-dependent stress response signaling and causes aneuploidy in Saccharomyces cerevisiae

苯代谢物氢醌诱导 Hog1 依赖性应激反应信号传导并导致酿酒酵母的非整倍性

DOI：
发表时间：
2010
期刊：
Journal of Radiation Research (in press)
影响因子：
0
作者：
堀美香;原島秀吉;紙谷浩之;Akira S.;Niraldo Paulino;Toshitaka Yamakawa;T. Tsuchiya;Takeki Shiga
通讯作者：
Takeki Shiga

Light-induced activation of class II cyclobutane pyrimidine dimer photolyases.

DOI：
10.1016/j.dnarep.2010.01.014
发表时间：
2010-05
期刊：
DNA repair
影响因子：
3.8
作者：
A. Okafuji;Till Biskup;K. Hitomi;E. Getzoff;G. Kaiser;A. Batschauer;A. Bacher;J. Hidema;Mika Teranishi;Kazuo Yamamoto;E. Schleicher;S. Weber
通讯作者：
A. Okafuji;Till Biskup;K. Hitomi;E. Getzoff;G. Kaiser;A. Batschauer;A. Bacher;J. Hidema;Mika Teranishi;Kazuo Yamamoto;E. Schleicher;S. Weber

Ames test-negative carcinogen, ortho-phenyl phenol, binds tubulin and causes aneuploidy in budding yeast.

艾姆斯试验阴性的致癌物质邻苯基苯酚与微管蛋白结合，导致芽殖酵母非整倍体。

DOI：
发表时间：
2007
期刊：
Mutat Res 617(1-2)
影响因子：
0
作者：
Hori M;Ishiguro C;Suzuki T;Nakagawa N;Nunoshiba T;Kuramitsu S;Yamamoto K.;Mika Hori;Tatsuo Nunoshiba
通讯作者：
Tatsuo Nunoshiba

KsgA, a 16S rRNA adenine methyltransferase, has a novel DNA glycosylase/AP lyase activity to prevent mutations in Escherichia coli.

DOI：
10.1093/nar/gkp057
发表时间：
2009-04
期刊：
Nucleic acids research
影响因子：
14.9
作者：
Zhang-Akiyama QM;Morinaga H;Kikuchi M;Yonekura S;Sugiyama H;Yamamoto K;Yonei S
通讯作者：
Yonei S

Base excision repair enzyme endonuclease III suppresses mutagenesis caused by 8-hydroxv-dGTP

碱基切除修复酶核酸内切酶 III 抑制 8-羟基-dGTP 引起的突变