Doxorubicin-induced Id2A gene transcription is targeted at an activating transcription factor/cyclic AMP response element motif through novel mechanisms involving protein kinases distinct from protein kinase C and protein kinase A
Doxorubicin-induced Id2A gene transcription is targeted at an activating transcription factor/cyclic AMP response element motif through novel mechanisms involving protein kinases distinct from protein kinase C and protein kinase A
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阿霉素诱导的 Id2A 基因转录通过涉及不同于蛋白激酶 C 和蛋白激酶 A 的蛋白激酶的新机制靶向激活转录因子/环 AMP 响应元件基序
DOI：
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发表时间：
1995
影响因子：
5.3
通讯作者：
L. Kedes
中科院分区：
文献类型：
--
作者：
M. Kurabayashi;S. Dutta;R. Jeyaseelan;L. Kedes
我们最近发现，阿霉素(Dox)是一种抗肿瘤药物，也是一种成肌和成脂细胞的终末分化抑制剂，它可以诱导ID的表达，ID是一种编码螺旋-环-螺旋转录抑制因子的基因。在这项研究中，我们研究了Dox诱导Id2A表达的分子机制。我们还试图确定对Dox的遗传反应是否与UV反应有关，UV反应是一组对UV和DNA损伤化合物的反应，部分由AP-1介导。瞬时转染人Id2A启动子序列的一系列缺失和点突变衍生物表明，两个与激活转录因子(ATF)结合位点或环状AMP反应元件(CRE)相似的紧密间隔和倒置的短元件是对Dox完全反应的必要条件和充分条件。我们将该元素称为IdATF站点。含有IdATF位点的序列赋予最小异源启动子Dox诱导性。电泳迁移率改变分析显示核蛋白与IdATF序列特异地相互作用。当含有合法的ATF/Cre或AP-1结合序列的寡核苷酸竞争结合时，抗体超移动实验表明，CREB/ATF-1和AP-1都不是与IdATF结合的主要因素。几个独立的标准表明，Dox的诱导性独立于钙/磷脂依赖的蛋白激酶(蛋白激酶C)、环磷酸腺苷依赖的蛋白激酶(蛋白激酶A)和酪氨酸激酶。此外，我们还发现Dox还通过AP-1非依赖的途径诱导即刻早期基因启动子的转录。综上所述，我们的结果表明Dox引起了一种不同于经典UV反应的新的遗传反应。
We have recently shown that doxorubicin (Dox), an antineoplastic drug and an inhibitor of terminal differentiation of myogenic and adipogenic cells, induces expression of Id, a gene encoding a helix-loop-helix transcriptional inhibitor. In this study we have investigated the molecular mechanisms underlying Dox-induced Id2A expression. We have also attempted to determine whether the genetic responses to Dox are related to the UV response, a well-characterized set of reactions to UV and DNA-damaging compounds that is partly mediated by AP-1. Transient transfection of a series of deletions and point mutation derivatives of the human Id2A promoter sequence shows that two closely spaced and inverted short elements similar to an activating transcription factor (ATF) binding site or a cyclic AMP response element (CRE) are necessary and sufficient for a full response to Dox. We refer to this element as the IdATF site. Sequences containing an IdATF site conferred Dox inducibility on a minimal heterologous promoter. An electrophoretic mobility shift assay showed nuclear proteins specifically interacting with the IdATF sequence. While oligonucleotides containing either legitimate ATF/CRE or AP-1 binding sequences competed for binding, antibody supershift experiments suggested that neither CREB/ATF-1 nor AP-1 are major factors binding to IdATF. Several independent criteria suggest that Dox inducibility was independent of Ca2+/phospholipid-dependent protein kinase (protein kinase C), cyclic AMP-dependent protein kinase (protein kinase A), and tyrosine kinase. Moreover, we found that Dox also induces transcription from promoters of immediate-early genes through an AP-1-independent pathway. Taken together, our results suggest that Dox elicits a novel genetic response distinct from the classical UV response.
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阿霉素-铁 (III) 复合物是蛋白激酶 C 的有效抑制剂。
DOI：
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发表时间：
1989
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Hannun,YA;Foglesong,RJ;Bell,RM
通讯作者：
Bell,RM
DOI：
10.1073/pnas.83.18.6682
发表时间：
1986-09-01
影响因子：
11.1
作者：
MONTMINY, MR;SEVARINO, KA;GOODMAN, RH
通讯作者：
GOODMAN, RH
DOI：
10.1073/pnas.83.21.8059
发表时间：
1986-11-01
影响因子：
11.1
作者：
MORGAN, RW;CHRISTMAN, MF;AMES, BN
通讯作者：
AMES, BN
人类骨骼α-肌动蛋白基因的核苷酸序列和表达：功能调节域的进化。
影响因子：
4.4
作者：
Taylor,A;Erba,HP;Muscat,GE;Kedes,L
通讯作者：
Kedes,L
影响因子：
56.9
作者：
DEVARY, Y;ROSETTE, C;KARIN, M
通讯作者：
KARIN, M