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题名: The function of ORAOV1/LTO1, a gene that is overexpressed frequently in cancer: essential roles in the function and biogenesis of the ribosome
作者: Zhai, C.1; Li, Y.1; Mascarenhas, C.2; Lin, Q.1; Li, K.1, 3; Vyrides, I.1; Grant, C. M.2; Panaretou, B.1
通讯作者: Panaretou, B (reprint author), Kings Coll London, Inst Pharmaceut Sci, Franklin Wilkins Bldg,150 Stamford St, London SE1 9NH, England.
关键词: ribosome biogenesis ; translation ; Fe - S cluster ; squamous cell carcinoma
刊名: ONCOGENE
发表日期: 2014-01-23
DOI: 10.1038/onc.2012.604
卷: 33, 期:4, 页:484-494
收录类别: SCI
文章类型: Article
部门归属: [Zhai, C.; Li, Y.; Lin, Q.; Li, K.; Vyrides, I.; Panaretou, B.] Kings Coll London, Inst Pharmaceut Sci, London SE1 9NH, England; [Mascarenhas, C.; Grant, C. M.] Univ Manchester, Fac Life Sci, Manchester, Lancs, England; [Li, K.] Chinese Acad Sci, Inst Hydrobiol, Wuhan, Peoples R China
WOS标题词: Science & Technology ; Life Sciences & Biomedicine
资助者: National Natural Science Foundation of China [31100057]
类目[WOS]: Biochemistry & Molecular Biology ; Oncology ; Cell Biology ; Genetics & Heredity
研究领域[WOS]: Biochemistry & Molecular Biology ; Oncology ; Cell Biology ; Genetics & Heredity
摘要: ORAOV1 (oral cancer overexpressed) is overexpressed in many solid tumours, making a key contribution to the development of cancer, but the cellular role of ORAOV1 is unknown. The yeast orthologue of this protein is encoded by the hitherto uncharacterized essential gene, YNL260c. Expression of ORAOV1 restores viability to yeast cells lacking YNL260c. Under nonpermissive conditions, our conditional mutants of YNL260c are defective in the maturation of the 60S ribosomal subunit, whereas maturation of the 40S subunit is unaffected. Also, initiation of translation is abrogated when YNL260c function is lost. YNL260c is indispensible for life in oxygen, but is nonessential under anaerobic conditions. Consequently, the toxic affects of aerobic metabolism on biogenesis and function of the ribosome are alleviated by YNL260c, hence, we rename YNL260c as LTO1; required for biogenesis of the large ribosomal subunit and initiation of translation in oxygen. Lto1 is found in a complex with Rli1/ABCE1, an ATP-binding cassette (ABC)-ATPase bearing N-terminal [4Fe - 4S] clusters. Like Lto1, the Rli1/ABCE1 [4Fe - 4S] clusters are not required for viability under anaerobic conditions, but are essential in the presence of oxygen. Loss of Lto1 function renders cells susceptible to hydroperoxide pro-oxidants, though this type of sensitivity is specific to certain types of oxidative stress as the lto1 mutants are not sensitive to an agent that oxidizes thiols. These findings reflect a functional interaction between Lto1 and the Rli1/ABCE1 [4Fe - 4S] clusters, as part of a complex, which relieves the toxic effects of reactive oxygen species (ROS) on biogenesis and function of the ribosome. This complex also includes Yae1, which bridges the interaction between Lto1 and Rli1/ABCE1. Interactions between members of this complex were demonstrated both in vivo and in vitro. An increased generation of ROS is a feature shared by many cancers. The ORAOV1 complex could prevent ROS-induced ribosomal damage, explaining why overexpression of ORAOV1 is so common in solid tumours.
英文摘要: ORAOV1 (oral cancer overexpressed) is overexpressed in many solid tumours, making a key contribution to the development of cancer, but the cellular role of ORAOV1 is unknown. The yeast orthologue of this protein is encoded by the hitherto uncharacterized essential gene, YNL260c. Expression of ORAOV1 restores viability to yeast cells lacking YNL260c. Under nonpermissive conditions, our conditional mutants of YNL260c are defective in the maturation of the 60S ribosomal subunit, whereas maturation of the 40S subunit is unaffected. Also, initiation of translation is abrogated when YNL260c function is lost. YNL260c is indispensible for life in oxygen, but is nonessential under anaerobic conditions. Consequently, the toxic affects of aerobic metabolism on biogenesis and function of the ribosome are alleviated by YNL260c, hence, we rename YNL260c as LTO1; required for biogenesis of the large ribosomal subunit and initiation of translation in oxygen. Lto1 is found in a complex with Rli1/ABCE1, an ATP-binding cassette (ABC)-ATPase bearing N-terminal [4Fe - 4S] clusters. Like Lto1, the Rli1/ABCE1 [4Fe - 4S] clusters are not required for viability under anaerobic conditions, but are essential in the presence of oxygen. Loss of Lto1 function renders cells susceptible to hydroperoxide pro-oxidants, though this type of sensitivity is specific to certain types of oxidative stress as the lto1 mutants are not sensitive to an agent that oxidizes thiols. These findings reflect a functional interaction between Lto1 and the Rli1/ABCE1 [4Fe - 4S] clusters, as part of a complex, which relieves the toxic effects of reactive oxygen species (ROS) on biogenesis and function of the ribosome. This complex also includes Yae1, which bridges the interaction between Lto1 and Rli1/ABCE1. Interactions between members of this complex were demonstrated both in vivo and in vitro. An increased generation of ROS is a feature shared by many cancers. The ORAOV1 complex could prevent ROS-induced ribosomal damage, explaining why overexpression of ORAOV1 is so common in solid tumours.
关键词[WOS]: YEAST SACCHAROMYCES-CEREVISIAE ; SQUAMOUS-CELL CARCINOMAS ; NUCLEAR EXPORT ; OXIDATIVE-STRESS ; GLOBAL ANALYSIS ; PROTEIN RLI1 ; ORAL-CANCER ; TRANSLATION ; 11Q13 ; ABCE1
语种: 英语
WOS记录号: WOS:000330214600009
ISSN号: 0950-9232
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内容类型: 期刊论文
URI标识: http://ir.ihb.ac.cn/handle/342005/20127
Appears in Collections:其他_期刊论文

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作者单位: 1.Kings Coll London, Inst Pharmaceut Sci, London SE1 9NH, England
2.Univ Manchester, Fac Life Sci, Manchester, Lancs, England
3.Chinese Acad Sci, Inst Hydrobiol, Wuhan, Peoples R China
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