Regulation of the Aurora-A gene following topoisomerase I inhibition: implication of the Myc transcription factor.
Regulation of the Aurora-A gene following topoisomerase I inhibition: implication of the Myc transcription factor.
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DOI：
10.1186/1476-4598-9-205
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发表时间：
2010-08-03
期刊：
影响因子：
37.3
通讯作者：
Barré B
中科院分区：
文献类型：
--
作者：
Courapied S;Cherier J;Vigneron A;Troadec MB;Giraud S;Valo I;Prigent C;Gamelin E;Coqueret O;Barré B
在细胞周期的G2期，Aurora-A激酶在中心体成熟和有丝分裂过程中起重要作用。在这项研究中，我们发现在结直肠细胞系中，Aurora-A的表达在拓扑异构酶I抑制后下调。使用染色质免疫沉淀分析，我们已经观察到，Myc转录因子和它的最大结合伙伴与极光-A启动子在细胞周期的G2期。RNA干扰实验表明Myc参与了Aurora-A基因的调控。拓扑异构酶I抑制后，Myc的表达下降，而Mad上调，Myc和Max与激酶启动子的关联被抑制。同时，在DNA上检测到Mad和Miz-1的增加的关联，与转录辅激活因子的募集的抑制相关。有趣的是，在sn 38处理后，在Aurora-A启动子上观察到H3 K9三甲基化和HP 1 γ募集的增加，表明该启动子位于遗传毒性处理后的SAHF病灶内。由于Aurora-A参与中心体成熟，我们观察到，正如预期的拓扑异构酶I抑制阻止中心体分离，但不影响其复制。因此，这导致G2停滞和衰老诱导。这些结果表明，Aurora-A基因被拓扑异构酶I抑制后的G2检查点失活的模型。因此，我们提出的假设，协调过度表达的Myc和Aurora-A，以及下调的Mad和Miz-1应作为一个预后的标志，拓扑异构酶I抑制剂的不良反应进行测试。
During the G2 phase of the cell cycle, the Aurora-A kinase plays an important role in centrosome maturation and progression to mitosis. In this study, we show in colorectal cell lines that Aurora-A expression is downregulated in response to topoisomerase I inhibition. Using chromatin immunoprecipitation assays, we have observed that the Myc transcription factor and its Max binding partner are associated with the Aurora-A promoter during the G2 phase of the cell cycle. RNA interference experiments indicated that Myc is involved in the regulation of the Aurora-A gene. Following topoisomerase I inhibition, the expression of Myc decreased whereas Mad was upregulated, and the association of Myc and Max with the promoter of the kinase was inhibited. In parallel, an increased association of Mad and Miz-1 was detected on DNA, associated with an inhibition of the recruitment of transcriptional coactivators. Interestingly, a gain of H3K9 trimethylation and HP1γ recruitment was observed on the Aurora-A promoter following sn38 treatment, suggesting that this promoter is located within SAHF foci following genotoxic treatment. Since Aurora-A is involved in centrosome maturation, we observed as expected that topoisomerase I inhibition prevented centrosome separation but did not affect their duplication. As a consequence, this led to G2 arrest and senescence induction. These results suggest a model by which the Aurora-A gene is inactivated by the G2 checkpoint following topoisomerase I inhibition. We therefore propose the hypothesis that the coordinated overexpression of Myc and Aurora-A, together with a downregulation of Mad and Miz-1 should be tested as a prognosis signature of poor responses to topoisomerase I inhibitors.
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影响因子：
8
作者：
Krystyniak, A;Garcia-Echeverria, C;Ferrari, S
通讯作者：
Ferrari, S
DOI：
10.1073/pnas.0804863106
发表时间：
2009-02-03
影响因子：
11.1
作者：
Basu, Suchitra;Liu, Qingquan;Dong, Fan
通讯作者：
Dong, Fan
影响因子：
16
作者：
Barre, Benjamin;Perkins, Neil D.
通讯作者：
Perkins, Neil D.
影响因子：
4.8
作者：
Barré, B;Vigneron, A;Coqueret, O
通讯作者：
Coqueret, O
影响因子：
64.5
作者：
Narita, M;Nunez, S;Lowe, SW
通讯作者：
Lowe, SW