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.

正苯基苯酚（OPP）及其肝代谢物苯基氢醌（PHQ）是广谱杀菌剂和抗菌剂。 OPP和PHQ在AMES系统中测试了阴性，并且在饮食中给药时大鼠泌尿膀胱中肿瘤的形成呈阳性，显示出非生物毒性致癌的特性。还已经证明，OPP和PHQ在体内或体外不结合或裂解DNA，而观察到OPP处理大鼠中剂量依赖性蛋白的结合。但是，OPP和PHQ会产生包括非整倍性在内的染色体畸变。因此，非生物毒性致癌物施加其作用的步骤需要阐明。在这项研究中，我们使用了酿酒酵母和培养的人类细胞中杂合性丧失（LOH）的测定法来确定OPP和PHQ的生物学作用。由于功能性染色体损失：非整倍性，因此发现LOH被OPP和PHQ诱导。 PHQ与微管蛋白在体外结合并干扰。我们进一步证明，由于SWE1（WEE1同源物）的稳定，PHQ可以在G2/M转变处停止细胞周期，这可能导致CDC28（CDK1/CDC2同源物）失活。此外，HOG1（p38 MAPK同源物）通过PHQ稳健地磷酸化，可以稳定SWE1。另一方面，CHK1和RAD53未用PHQ磷酸化，表明MEC1/Tel1 DNA损伤检查点不起作用。 SWE1和HOG1的突变消除了G2/M过渡时PHQ诱导的停滞，并具有对PHQ致死性和非整倍性形成的抵抗力。这些结果表明，由HOG1-SWE1途径激活的PHQ诱导的G2/M转变检查点在非整倍性的形成中起作用。我们认为OPP和PHQ激活MAPK途径在G2/M转变时捕获细胞周期，并引起非整倍性。

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）

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

Induction of mitotic delay, apoptosis and aneuploidy in human cells by phenyl hydroquinone, an Ames test-negative carcinogen

苯对苯二酚（一种艾姆斯试验阴性致癌物）可诱导人体细胞有丝分裂延迟、细胞凋亡和非整倍性

DOI：
发表时间：
2009
期刊：
Gene and Genetic Systems 84
影响因子：
0
作者：
Kubota;N.;T.Ebihara;M.Matsumoto;S.Gando;T.Seya;Masaru Imai
通讯作者：
Masaru Imai

The native cyclobutane pyrimidine dimer photolyase of rice is phosohorylated

水稻的天然环丁烷嘧啶二聚体光裂合酶被磷酸化

DOI：
发表时间：
2008
期刊：
Plant Physiology 146
影响因子：
0
作者：
Du;J.;Shirakawa;H.;Han;J.;Imura;H;Mika Teranishi
通讯作者：
Mika Teranishi

Phenyl hydroquinone, Ames test-negative carcinogen, induces Hogl-dependent stress response signaling ; implication for aneuploidy development in Saccharomvces cerevisiae

苯基对苯二酚，Ames 试验阴性致癌物，诱导 Hogl 依赖性应激反应信号传导；

DOI：
发表时间：
2008
期刊：
FEBS Journal 275
影响因子：
0
作者：
Tauchi;H.;Waku;H.;Matumoto;E.;Yara;S.;Okumura;S.;Iwata,Y.;Komatsu;K.;Frusawa;Y.;Eguchi-Kasai;K.;Tachibana;A.;Ayumi Yamamoto
通讯作者：
Ayumi Yamamoto

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