Genomic Collaboration of Estrogen Receptor α and Extracellular Signal-Regulated Kinase 2 in Regulating Gene and Proliferation Programs
Genomic Collaboration of Estrogen Receptor α and Extracellular Signal-Regulated Kinase 2 in Regulating Gene and Proliferation Programs
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DOI：
10.1128/mcb.00821-10
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发表时间：
2011-01-01
影响因子：
5.3
通讯作者：
Katzenellenbogen, Benita S.
中科院分区：
文献类型：
--
作者：
Madak-Erdogan, Zeynep;Lupien, Mathieu;Katzenellenbogen, Benita S.
核激素受体、雌激素受体α（ER α）和丝裂原活化蛋白激酶（MAPK）在肿瘤依赖性癌症中起关键作用，但它们的相互作用和信号输入的整合仍然知之甚少。在这些研究中，我们记录了雌激素占据的ER α激活并与细胞外信号调节激酶2（ERK 2）相互作用，ERK 2是MAPK通路的下游效应子，导致ERK 2和ER α在乳腺癌细胞基因组的染色质结合位点共定位。这种基因组共定位，主要是在保守的远端增强子位点，需要激活ER α和ERK 2，并使ERK 2调节雌激素依赖性基因表达和增殖程序。ERK 2底物CREB 1也被激活，并在雌激素处理后被招募到ERK 2结合的染色质，并发现与ER α/ERK 2在调节基因转录和细胞周期进程中合作。我们的研究揭示了一种新的范式，在染色质水平上ERK 2和ER α的融合使这种激酶以关键和直接的方式支持核受体活性，这种合作模式也可能是其他核受体对基因表达的MAPK调控的基础。
The nuclear hormone receptor, estrogen receptor alpha (ER alpha), and mitogen-activated protein kinases (MAPKs) play key roles in hormone-dependent cancers, and yet their interplay and the integration of their signaling inputs remain poorly understood. In these studies, we document that estrogen-occupied ER alpha activates and interacts with extracellular signal-regulated kinase 2 (ERK2), a downstream effector in the MAPK pathway, resulting in ERK2 and ER alpha colocalization at chromatin binding sites across the genome of breast cancer cells. This genomic colocalization, predominantly at conserved distal enhancer sites, requires the activation of both ER alpha and ERK2 and enables ERK2 modulation of estrogen-dependent gene expression and proliferation programs. The ERK2 substrate CREB1 was also activated and recruited to ERK2-bound chromatin following estrogen treatment and found to cooperate with ER alpha/ERK2 in regulating gene transcription and cell cycle progression. Our study reveals a novel paradigm with convergence of ERK2 and ER alpha at the chromatin level that positions this kinase to support nuclear receptor activities in crucial and direct ways, a mode of collaboration likely to underlie MAPK regulation of gene expression by other nuclear receptors as well.