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Role of ER stress sensor Bip/GRP78 in protection of genome stability from DNA damaging stresses

ER 应激传感器 Bip/GRP78 在保护基因组稳定性免受 DNA 损伤应激中的作用

基本信息

批准号：
15510043
负责人：
KITA Kazuko
金额：
$ 2.5万
依托单位：
Chiba University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15510043/
关键词：
ER stress proteins Bip GRP78 DNA damage UV human cells sensitivity to cell death DNA repair molecular chaperone 遺伝子変異誘導

项目摘要

In contrast to extensive studies on the roles of molecular chaperones in mammalian cell responses to DNA-damaging stresses, there are only a few reports about the roles of Bip/GRP78, an endoplasmic reticulum(ER) stress-induced molecular chaperone. To investigate whether Bip/GRP78 is involved in resistance to a DNA-damaging agent, UVC (principally 254 nm in wavelength), we established human cells with down-regulation of Bip/GRP78 by transaction of human RSa cells with antisense cDNA for Bip/GRP. We found that the transfected cells showed higher sensitivity to UVC-induced cell death than control cells transfected with the vector alone. In the antisense-cDNA transfected cells, the removal capacities of the two major types of UVC-damaged DNA (thymine dimers and (6-4) photoproducts) in vivo and DNA synthesis activity of whole cell extracts to repair UVC-irradiated plasmids in vitro were remarkably decreased compared with those in the control cells. Furthermore, the antisense-cDNA transfected cells also showed slightly higher sensitivity to cisplatin-induced cell death than the control cells. Cisplatin-induced DNA damage is primarily repaired by nucleotide excision repair, like UVC-induced DNA damage. The present results suggest that Bip/GRP78 plays a protective role against UVC-induced cell death possibly via nucleotide excision repair, at least in the human RSa cells tested.

与分子伴侣在哺乳动物细胞DNA损伤应激反应中的作用的广泛研究相比，只有少数报道Bip/GRP 78，内质网（ER）应激诱导的分子伴侣的作用。为了研究Bip/GRP 78是否参与对DNA损伤剂UVC（主要波长为254 nm）的抗性，我们通过用Bip/GRP的反义cDNA处理人RSa细胞来建立Bip/GRP 78下调的人细胞。我们发现，转染的细胞表现出更高的敏感性，紫外线诱导的细胞死亡比对照细胞单独转染的载体。在反义cDNA转染的细胞中，两种主要类型的紫外线损伤的DNA（胸腺嘧啶二聚体和（6-4）光产物）在体内的清除能力和DNA合成活性的全细胞提取物修复紫外线照射的质粒在体外显着降低与对照细胞相比。此外，反义cDNA转染的细胞也表现出比对照细胞稍高的敏感性顺铂诱导的细胞死亡。顺铂诱导的DNA损伤主要通过核苷酸切除修复来修复，类似于UV C诱导的DNA损伤。目前的结果表明，Bip/GRP 78可能通过核苷酸切除修复对UV C诱导的细胞死亡起保护作用，至少在测试的人RSa细胞中是如此。

项目成果

期刊论文数量（48）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Induction of uPA release in human peripheral blood lymphocytes by [deamino-Cys1,D-Arg8]-vasopressin (dDAVP).

[脱氨基-Cys1,D-Arg8]-加压素 (dDAVP) 诱导人外周血淋巴细胞释放 uPA。

DOI：
发表时间：
2004
期刊：
Am.J.Phsiol Endocrinol Metab. 287
影响因子：
0
作者：
Yamaguchi;Y.;Yamada;K.;Suzuki;T.;Wu Y-P.;Kita K.;Takahashi;S.;Ichinose;M.;Suzuki;N.
通讯作者：
N.

Involvement of LEU13 in interferon-induced refractoriness of human RSa cells to X-ray cell killing.

LEU13 参与干扰素诱导的人 RSa 细胞对 X 射线细胞杀伤的抵抗力。