Ras/MAPK signaling modulates VEGFR-3 expression through Ets-mediated p300 recruitment and histone acetylation on the Vegfr3 gene in lymphatic endothelial cells.
Ras/MAPK signaling modulates VEGFR-3 expression through Ets-mediated p300 recruitment and histone acetylation on the Vegfr3 gene in lymphatic endothelial cells.
复制标题
DOI：
10.1371/journal.pone.0051639
复制
发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Ichise H
中科院分区：
文献类型：
--
作者：
Ichise T;Yoshida N;Ichise H
VEGFR-3 表达的调节对于改变发育、生理和病理条件下发生的淋巴管生成过程中的淋巴管内皮细胞 (LEC) 特征非常重要。然而，Vegfr3 基因表达调节的机制仍然很大程度上未知。使用基因工程小鼠和 LEC，我们之前证明 Ras 信号传导不仅参与 VEGFR-3 诱导的信号转导，而且还参与 Vegfr3 基因表达。在这里，我们研究了 LEC 中转录因子 Ets 和组蛋白乙酰转移酶 p300 在 Ras 介导的 Vegfr3 转录调控中的作用。 Ras 通过 MAPK 诱导的磷酸化激活 Ets 蛋白。 Ets 敲低与 Ras 敲低类似，会导致 Vegfr3 转录水平和 Vegfr3 基因上的乙酰化组蛋白 H3 降低。 Vegfr3 敲低会导致 LEC 表型改变，例如异常细胞增殖和网络形成，而 Ets 敲低则导致较温和但相似的表型变化。我们在 Vegfr3 基因内发现了进化上保守的非编码调控元件，这些元件含有 Ets 结合基序并在 LEC 中具有增强子活性。染色质免疫沉淀 (ChIP) 分析显示，Ras 和 Ets 敲低后，Vegfr3 基因调控元件上的乙酰化组蛋白 H3 减少，并且激活的 Ets 蛋白与 p300 一起与这些调控元件相关，这与 p300 敲低 LEC 中 Vegfr3 基因表达的减少一致。我们的研究结果证明了 Ras 信号传导与 Ets 和 p300 介导的 Vegfr3 转录调节之间的联系，并提供了在淋巴管生成过程中调节 VEGFR-3 表达水平的潜在机制。
Modulation of VEGFR-3 expression is important for altering lymphatic endothelial cell (LEC) characteristics during the lymphangiogenic processes that occur under developmental, physiological, and pathological conditions. However, the mechanisms underlying the modulation of Vegfr3 gene expression remain largely unknown. Using genetically engineered mice and LECs, we demonstrated previously that Ras signaling is involved not only in VEGFR-3-induced signal transduction but also in Vegfr3 gene expression. Here, we investigated the roles of the transcription factor Ets and the histone acetyltransferase p300 in LECs in Ras-mediated transcriptional regulation of Vegfr3. Ras activates Ets proteins via MAPK-induced phosphorylation. Ets knockdown, similar to Ras knockdown, resulted in a decrease in both Vegfr3 transcript levels and acetylated histone H3 on the Vegfr3 gene. Vegfr3 knockdown results in altered LEC phenotypes, such as aberrant cell proliferation and network formation, and Ets knockdown led to milder but similar phenotypic changes. We identified evolutionarily conserved, non-coding regulatory elements within the Vegfr3 gene that harbor Ets-binding motifs and have enhancer activities in LECs. Chromatin immunoprecipitation (ChIP) assays revealed that acetylated histone H3 on the regulatory elements of the Vegfr3 gene was decreased following Ras and Ets knockdown, and that activated Ets proteins, together with p300, were associated with these regulatory elements, consistent with a reduction in Vegfr3 gene expression in p300-knockdown LECs. Our findings demonstrate a link between Ras signaling and Ets- and p300-mediated transcriptional regulation of Vegfr3, and provide a potential mechanism by which VEGFR-3 expression levels may be modulated during lymphangiogenesis.
登录
查看更多内容
DOI：
10.1093/jnci/94.11.819
发表时间：
2002-06-05
期刊：
JOURNAL OF THE NATIONAL CANCER INSTITUTE
影响因子：
--
作者：
He, YL;Kozaki, KI;Alitalo, K
通讯作者：
Alitalo, K
影响因子：
3.3
作者：
Mishima, Koichi;Watabe, Tetsuro;Miyazono, Kohei
通讯作者：
Miyazono, Kohei
影响因子：
64.5
作者：
ONEILL, EM;REBAY, I;RUBIN, GM
通讯作者：
RUBIN, GM
影响因子：
64.8
作者：
BRUNNER, D;DUCKER, K;KLAMBT, C
通讯作者：
KLAMBT, C
影响因子：
30.5
作者：
Karkkainen, MJ;Haiko, P;Alitalo, K
通讯作者：
Alitalo, K