Dannenberg-independent Mechanisms Transcription by CREB-binding Protein / p 300-dependent and Retinoids and Carnosol Suppress Cyclooxygenase-2 Updated Version
Dannenberg-independent Mechanisms Transcription by CREB-binding Protein / p 300-dependent and Retinoids and Carnosol Suppress Cyclooxygenase-2 Updated Version
复制标题
CREB 结合蛋白 / p 300 依赖性的 Dannenberg 独立转录机制以及类视黄醇和鼠尾草酚抑制环加氧酶 2 更新版本
DOI：
--
复制
发表时间：
2002
期刊：
影响因子：
--
通讯作者：
A. Dannenberg
中科院分区：
文献类型：
--
作者：
K. Subbaramaiah;P. Cole;A. Dannenberg
维甲酸（RA）或鼠尾草醇（carnosol）这两种结构无关但具有抗癌特性的化合物，可抑制phopbol酯（PMA）介导的人乳腺上皮细胞中活化蛋白1 （AP-1）活性和环氧合酶2 （COX-2）表达。PMA诱导COX-2转录是通过增加AP-1与COX-2启动子环AMP响应元件（CRE）的结合介导的。抑制crebp /p300的组蛋白乙酰转移酶活性可阻断PMA对COX-2的诱导。用鼠尾草醇而非RA治疗可阻断AP-1与COX-2启动子结合的增加。由于AP-1的结合不受RA的影响，我们研究了RA是否通过影响协激活子CBP/p300来抑制COX-2的转录。RA治疗刺激了RA受体与CBP/p300之间的相互作用；CBP/p300与c-Jun的相互作用相应降低。重要的是，过表达CBP/p300或显性阴性RA受体可减轻RA对pma介导的COX-2启动子刺激的抑制作用。为了阐明鼠油醇抑制COX-2转录的机制，研究了鼠油醇对蛋白激酶C （PKC）信号传导的影响。鼠尾草醇抑制PKC、ERK1/2、p38和c-Jun nh2末端激酶有丝分裂原活化蛋白激酶的激活，而RA不抑制。过表达c-Jun而非CBP/p300逆转了鼠尾草醇对pma介导的COX-2启动子活性刺激的抑制作用。因此，RA通过受体依赖机制来限制可用于ap -1介导的COX-2诱导的CBP/p300的数量。相比之下，鼠油醇通过阻断PKC信号传导从而抑制AP-1与COX-2启动子的CRE结合来抑制COX-2的诱导。综上所述，这些结果表明小分子可以通过不同的机制阻断COX-2转录的激活。
Treatment with retinoic acid (RA) or carnosol, two structurally unrelated compounds with anticancer properties, inhibited phorbol ester (PMA)-mediated induction of activator protein-1 (AP-1) activity and cyclooxygenase-2 (COX-2) expression in human mammary epithelial cells. The induction of COX-2 transcription by PMA was mediated by increased binding of AP-1 to the cyclic AMP response element (CRE) of the COX-2 promoter. Inhibition of the histone acetyltransferase activity of CREBbinding protein (CBP)/p300 blocked the induction of COX-2 by PMA. Treatment with carnosol but not RA blocked increased binding of AP-1 to the COX-2 promoter. Because AP-1 binding was unaffected by RA, we investigated whether RA inhibited COX-2 transcription via effects on the coactivator CBP/p300. Treatment with RA stimulated an interaction between RA receptorand CBP/p300; a corresponding decrease in the interaction between CBP/p300 and c-Jun was observed. Importantly, overexpressing CBP/p300 or dominant-negative RA receptorrelieved the suppressive effect of RA on PMA-mediated stimulation of the COX-2 promoter. To elucidate the mechanism by which carnosol inhibited COX-2 transcription, its effects on protein kinase C (PKC) signaling were determined. Carnosol but not RA inhibited the activation of PKC, ERK1/2, p38, and c-Jun NH2-terminal kinase mitogen-activated protein kinase. Overexpressing c-Jun but not CBP/p300 reversed the suppressive effect of carnosol on PMA-mediated stimulation of COX-2 promoter activity. Thus, RA acted by a receptor-dependent mechanism to limit the amount of CBP/p300 that was available for AP-1-mediated induction of COX-2. By contrast, carnosol inhibited the induction of COX-2 by blocking PKC signaling and thereby the binding of AP-1 to the CRE of the COX-2 promoter. Taken together, these results show that small molecules can block the activation of COX-2 transcription by distinct mechanisms.
登录
查看更多内容
选择性环氧合酶 2 抑制剂可抑制 H-ras 转化的大鼠肠上皮细胞的生长。
影响因子：
29.4
作者：
Sheng,GG;Shao,J;Sheng,H;Hooton,EB;Isakson,PC;Morrow,JD;CoffeyJr,RJ;DuBois,RN;Beauchamp,RD
通讯作者：
Beauchamp,RD
DOI：
--
发表时间：
2001-02
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Swati Kulkarni;J. Rader;Fan Zhang;H. Liapis;A. Koki;J. Masferrer;K. Subbaramaiah;A. Dannenberg
通讯作者：
Swati Kulkarni;J. Rader;Fan Zhang;H. Liapis;A. Koki;J. Masferrer;K. Subbaramaiah;A. Dannenberg
影响因子：
11.2
作者：
H. Sheng;J. Shao;J. Morrow;R. Beauchamp;R. Dubois
通讯作者：
H. Sheng;J. Shao;J. Morrow;R. Beauchamp;R. Dubois
DOI：
10.1016/s0021-9258(18)98774-0
发表时间：
1991-07
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
D. Kujubu;B. Fletcher;B. Varnum;R. Lim;H. Herschman
通讯作者：
D. Kujubu;B. Fletcher;B. Varnum;R. Lim;H. Herschman
影响因子：
11.2
作者：
J. Mestre;K. Subbaramaiah;P. Sacks;S. Schantz;T. Tanabe;H. Inoue;A. Dannenberg
通讯作者：
J. Mestre;K. Subbaramaiah;P. Sacks;S. Schantz;T. Tanabe;H. Inoue;A. Dannenberg