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

• 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

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对 DNA 损伤应激反应中的作用的广泛研究相反，有关内质网 (ER) 应激诱导分子伴侣 Bip/GRP78 的作用的报道很少。为了研究 Bip/GRP78 是否参与对 DNA 损伤剂 UVC（主要是波长 254 nm）的抵抗，我们通过将 Bip/GRP78 的反义 cDNA 与人 RSa 细胞进行交易，建立了 Bip/GRP78 下调的人细胞。总生产总值。我们发现转染的细胞比单独转染载体的对照细胞对 UVC 诱导的细胞死亡表现出更高的敏感性。在反义 cDNA 转染细胞中，两种主要类型的 UVC 损伤 DNA（胸腺嘧啶二聚体和 (6-4) 光产物）的体内去除能力以及全细胞提取物在体外修复 UVC 照射质粒的 DNA 合成活性与对照细胞相比显着降低。此外，反义cDNA转染的细胞还表现出比对照细胞对顺铂诱导的细胞死亡稍高的敏感性。顺铂诱导的 DNA 损伤主要通过核苷酸切除修复来修复，就像 UVC 诱导的 DNA 损伤一样。目前的结果表明，Bip/GRP78 可能通过核苷酸切除修复对 UVC 诱导的细胞死亡发挥保护作用，至少在测试的人类 RSa 细胞中是这样。

项目成果

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。

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

Kita, K., Sugaya, S., Zhai, L., Wu, YP., Wano, C., Chigira, S., Nomura, J., Takahashi, S., Ichinose, M., Suzuki, N.: "Involvement of Leu-13 in interferon-induced refractoriness of human RSa cells to X-ray cell killing."Radiat.Res.. 160. 302-308 (2003)

Kita, K.、Sugaya, S.、Zhai, L.、Wu, YP.、Wano, C.、Chigira, S.、Nomura, J.、Takahashi, S.、Ichinose, M.、Suzuki, 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。

• 发表时间: 2003
• 期刊: Radiat.Res. 160
• 作者: Kita;K.;Sugaya;S.;Zhai;L.;Wu;Y.;Wano;C.;Chigira;S.;Nomura;J.;Takahashi;S.;Ichinose;M.;Suzuki;N.
• 通讯作者: N.

Hasegawa, R., Kita, K., Hasegawa, R., Fusejima, K., Fukazawa, S., Wano, C., Watanabe, S., Saisho, H., Masuda, Y., Nomura, F., Suzuki, N.: "Induction of apoptosis and ubiquitin hydrolase gene expression by human serum factors in the early phase of acute my

长谷川，R.，北，K.，长谷川，R.，布岛，K.，深泽，S.，和野，C.，渡边，S.，Saisho，H.，增田，Y.，野村，F.，

Increased levels of UV-induced protease activity in human UVAP-1 cells exposed to gravity-changing stress : involvement of E-64-sensitive proteases on suppression of UV mutagenicity.

暴露于重力变化应激的人 UVAP-1 细胞中紫外线诱导的蛋白酶活性水平增加：E-64 敏感蛋白酶参与抑制紫外线致突变性。

• 发表时间: 2003
• 期刊: Cell Biol.Int. 27
• 作者: Takahashi;S.;Hasegawa;R.;Kita;K.;Zhang;H-C.;Wano;C.;Yamaguchi;Y.;Sugaya;S.;Nomura;J.;Ichinose;M.;Suzuki;N.
• 通讯作者: N.