Steroid receptor coactivator-3 and activator protein-1 coordinately regulate the transcription of components of the insulin-like growth factor/AKT signaling pathway
Steroid receptor coactivator-3 and activator protein-1 coordinately regulate the transcription of components of the insulin-like growth factor/AKT signaling pathway
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DOI：
10.1158/0008-5472.can-06-2442
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发表时间：
2006-11-15
期刊：
影响因子：
11.2
通讯作者：
Tsai, Ming-Jer
中科院分区：
文献类型：
--
作者：
Yan, Jun;Yu, Cheng-Tai;Tsai, Ming-Jer
类固醇受体共激活因子(SRC)-3在乳腺癌中也被称为扩增1，是p160核受体共激活因子家族的一员，参与靶基因的转录调控。SRC-3在激素敏感和激素不敏感的肿瘤中经常扩增和/或过表达。我们之前报道SRC-3通过激活AKT信号通路以激素不依赖的方式刺激前列腺细胞生长。然而，其潜在机制仍未明确。在这里,我们!利用本实验室生成的米非司酮诱导SRC-3 LNCaP前列腺癌细胞系，通过寡核苷酸芯片分析鉴定SRC-3调控基因。我们发现SRC-3上调胰岛素样生长因子(IGF)/AKT信号通路中参与细胞增殖和存活的多个基因的表达。相反，在PC3（雄激素受体阴性）前列腺癌细胞和MCF-7乳腺癌细胞中，SRC-3的敲低会降低其表达。同样，在SRC-3缺失小鼠的前列腺中，IGF/AKT信号通路中这些成分的表达也减少。染色质免疫沉淀实验显示，SRC-3被直接募集到这些基因的启动子上，表明它们是SRC-3的直接靶点。有趣的是，我们发现SRC-3募集到两个目标启动子IRS-2和IGF-I，需要转录因子激活蛋白1 （AP-1）。综上所述，我们的研究结果清楚地表明，SRC-3和AP-1可以协同调节IGF/AKT通路中多个组分的转录，以确保不依赖配体的癌细胞增殖和存活。
Steroid receptor coactivator (SRC)-3, also called amplified in breast cancer 1, is a member of the p160 nuclear receptor coactivator family involved in transcriptional regulation of target genes. SRC-3 is frequently amplified and/or overexpressed in hormone-sensitive and hormone-insensitive tumors. We reported previously that SRC-3 stimulated prostate cell growth in a hormone-independent manner through activation of AKT signaling pathway. However, the underlying mechanism remains undefined. Here, we! exploited the mifepristone-induced SRC-3 LNCaP prostate cancer cell line generated in our laboratory to identify SRC-3-regulated genes by oligonucleotide microarray analysis. We found that SRC-3 up-regulates the expression of multiple genes in the insulin-like growth factor (IGF)/AKT signaling pathway that are involved in cell proliferation and survival. In contrast, knockdown of SRC-3 in PC3 (androgen receptor negative) prostate cancer cells and MCF-7 breast cancer cells reduces their expression. Similarly, in prostate glands of SRC-3 null mice, expressions of these components in the IGF/AKT signal pathway are also reduced. Chromatin immunoprecipitation assay revealed that SRC-3 was directly recruited to the promoters of these genes, indicating that they are direct targets of SRC-3. Interestingly, we showed that recruitment of SRC-3 to two target promoters, IRS-2 and IGF-I, requires transcription factor activator protein-1 (AP-1). Taken together, our results clearly show that SRC-3 and AP-1 can coordinately regulate the transcription of multiple components in the IGF/AKT pathway to ensure ligand-independent cell proliferation and survival of cancer cells.