The mir-34 microRNA is required for the DNA damage response in vivo in C. elegans and in vitro in human breast cancer cells.
The mir-34 microRNA is required for the DNA damage response in vivo in C. elegans and in vitro in human breast cancer cells.
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DOI：
10.1038/onc.2009.106
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发表时间：
2009-06-25
期刊：
影响因子：
8
通讯作者：
Slack, F. J.
中科院分区：
文献类型：
--
作者：
Kato, M.;Paranjape, T.;Ullrich, R.;Nallur, S.;Gillespie, E.;Keane, K.;Esquela-Kerscher, A.;Weidhaas, J. B.;Slack, F. J.
MicroRNA (miRNA) 是细胞命运决定和体内平衡的重要调节因子。这些小 RNA 基因的表达在发育过程中和正常组织中受到严格调控，但它们在癌症中常常受到错误调控。 miRNA 表达也会受到 DNA 损伤剂（例如辐射）的影响。特别是，哺乳动物的 miR-34 在辐射反应中被 p53 上调，但人们对这种 miRNA 在体内的作用知之甚少。在这里，我们发现，具有 mir-34 基因功能丧失突变的秀丽隐杆线虫对辐射具有异常的细胞生存反应；这些动物的体细胞对辐射高度敏感，而种系对辐射具有抗性。这些发现表明 mir-34 在体内凋亡和非凋亡细胞死亡中的作用，与线虫 p53 同源物 cep-1 的作用非常相似。这些结果还在乳腺癌细胞中得到了体外验证，其中外源添加 miR-34 会改变辐射后的细胞存活率。这些观察结果证实，miR-34是体内对DNA损伤的正常细胞反应所必需的，导致辐射后细胞存活的改变，并指出抗miR-34作为p53突变乳腺癌的放射增敏剂的潜在治疗用途。
MicroRNAs (miRNAs) are important regulators of cell fate determination and homeostasis. Expression of these small RNA genes is tightly regulated during development and in normal tissues, but they are often misregulated in cancer. MiRNA expression is also affected by DNA damaging agents, such as radiation. In particular, mammalian miR-34 is upregulated by p53 in response to radiation, but little is known about the role of this miRNA in vivo. Here we show that Caenorhabditis elegans with loss-of-function mutations in the mir-34 gene have an abnormal cellular survival response to radiation; these animals are highly radiosensitive in the soma and radioresistant in the germline. These findings show a role for mir-34 in both apoptotic and non-apoptotic cell death in vivo, much like that of cep-1, the C. elegans p53 homolog. These results have been additionally validated in vitro in breast cancer cells, wherein exogenous addition of miR-34 alters cell survival post-radiation. These observations confirm that mir-34 is required for a normal cellular response to DNA damage in vivo resulting in altered cellular survival post-irradiation, and point to a potential therapeutic use for anti-miR-34 as a radiosensitizing agent in p53-mutant breast cancer.
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影响因子：
8
作者：
Hui, L.;Zheng, Y.;Foster, D. A.
通讯作者：
Foster, D. A.
影响因子：
16
作者：
Gartner, A;Milstein, S;Hengartner, MO
通讯作者：
Hengartner, MO
影响因子：
11.2
作者：
Iorio, MV;Ferracin, M;Croce, CM
通讯作者：
Croce, CM
影响因子：
11.2
作者：
Johnson, Charles D.;Esquela-Kerscher, Aurora;Slack, Frank J.
通讯作者：
Slack, Frank J.
DOI：
10.1073/pnas.88.23.10657
发表时间：
1991-12-01
影响因子：
11.1
作者：
RUNNEBAUM, IB;NAGARAJAN, M;SUKUMAR, S
通讯作者：
SUKUMAR, S