Distinct roles of the steroid receptor coactivator 1 and of MED1 in retinoid-induced transcription and cellular differentiation
Distinct roles of the steroid receptor coactivator 1 and of MED1 in retinoid-induced transcription and cellular differentiation
复制标题
DOI：
10.1074/jbc.m603023200
复制
发表时间：
2006-07-21
影响因子：
4.8
通讯作者：
Lefebvre, Philippe
中科院分区：
文献类型：
--
作者：
Flajollet, Sebastien;Lefebvre, Bruno;Lefebvre, Philippe
视黄酸受体（RARs）是类视黄酸作用于转录、细胞分化和细胞凋亡的分子传导体。类视黄酮调节的启动子的转录激活需要释放辅抑制子和招募辅激活子来结合启动子的RAR。RARs在体外招募过多的共激活因子，其对类维甲酸诱导的转录的实际贡献在体内尚不清楚。胚胎癌P19细胞对类维生素a高度敏感，通过RNAi去除典型的共激活因子。SRC1缺失的P19细胞表现出严重受损的类维甲酸诱导反应，这与SRC1作为RAR共激活因子的假设作用一致。出乎意料的是，Med1/TRAP220/ drip205缺失的细胞在转录反应和细胞分化方面都表现出对类维生素a的加剧反应。Med1缺失影响了典型类视黄酮调控的RAR β 2启动子的TFIIH和cdk9检测，并有利于RAR β 2基因转录区域的RNA聚合酶II检测。此外，配体的性质强烈影响RARs与给定的辅激活子相互作用的能力，并在完整细胞中激活转录。因此，RAR作为配体结构的一种功能，通过招募控制类视黄酮调节启动子中不同分子事件的调节复合体来完成转录激活。
Retinoic acid receptors (RARs) are the molecular relays of retinoid action on transcription, cellular differentiation and apoptosis. Transcriptional activation of retinoid-regulated promoters requires the dismissal of corepressors and the recruitment of coactivators to promoter-bound RAR. RARs recruit in vitro a plethora of coactivators whose actual contribution to retinoid-induced transcription is poorly characterized in vivo. Embryonal carcinoma P19 cells, which are highly sensitive to retinoids, were depleted from archetypical coactivators by RNAi. SRC1-deficient P19 cells showed severely compromised retinoid-induced responses, in agreement with the supposed role of SRC1 as a RAR coactivator. Unexpectedly, Med1/TRAP220/DRIP205-depleted cells exhibited an exacerbated response to retinoids, both in terms transcriptional responses and of cellular differentiation. Med1 depletion affected TFIIH and cdk9 detection at the prototypical retinoid-regulated RAR beta 2 promoter, and favored a higher RNA polymerase II detection in transcribed regions of the RAR beta 2 gene. Furthermore, the nature of the ligand impacted strongly on the ability of RARs to interact with a given coactivator and to activate transcription in intact cells. Thus RAR accomplishes transcriptional activation as a function of the ligand structure, by recruiting regulatory complexes which control distinct molecular events at retinoid-regulated promoters.