Dickkopf homolog 1, a Wnt signaling antagonist, is transcriptionally up-regulated via an ATF4-independent and MAPK/ERK-dependent pathway following amino acid deprivation.
Dickkopf homolog 1, a Wnt signaling antagonist, is transcriptionally up-regulated via an ATF4-independent and MAPK/ERK-dependent pathway following amino acid deprivation.
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DOI：
10.1016/j.bbagrm.2011.05.016
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发表时间：
2011-07
影响因子：
4.7
通讯作者：
Chen, Hong
中科院分区：
文献类型：
--
作者：
Zhou, Dan;Zhang, Yukun;Pan, Yuan-Xiang;Chen, Hong
当细胞缺乏氨基酸时，氨基酸反应（AAR）途径被激活。在本研究中，使用人结肠癌细胞系SW 480，我们观察到，DKK 1，Wnt通路的拮抗剂，在mRNA水平显着诱导后，从培养基中去除氨基酸。添加氨基醇组氨醇（其防止组氨酰-tRNAHis的形成）也将DKK 1 mRNA增加至与细胞被剥夺所有氨基酸时观察到的水平相似的水平。在氨基酸剥夺条件下，DKK 1 mRNA的转录活性和稳定性均增加。通过在氨基酸剥夺条件下DKK 1蛋白的免疫荧光染色增加来证实DKK 1基因表达的诱导。虽然染色质免疫沉淀试验显示，在氨基酸限制条件下，DKK 1启动子处的RNA聚合酶II结合增加，但不存在与启动子结合的ATF 4。荧光素酶报告基因检测未检测到DKK 1基因结构内的任何功能性AARE。通过siRNA敲低ATF 4并不影响氨基酸限制期间DKK 1 mRNA的增加。ERK磷酸化的抑制消除了DKK 1的诱导。我们的研究表明，DKK 1是一个新的靶基因在响应氨基酸缺乏和DKK 1的表达上调通过一个ATF 4-非依赖性和ERK-依赖性途径。
Amino acid response (AAR) pathway is activated when cells are deprived of amino acids. In the present study, using the human colon cancer cell line SW480, we observed that DKK1, an antagonist of the Wnt pathway, was significantly induced at the mRNA level after the removal of amino acids from the medium. Addition of the amino alcohol histidinol, which prevents the formation of histidinyl-tRNAHis, also increased DKK1 mRNA to a level similar to that observed when cells were deprived of all amino acids. Transcriptional activity and stability of DKK1 mRNA were both increased in the amino acid-deprived condition. The induction of DKK1 gene expression was confirmed by the increased immunofluorescent staining of the DKK1 protein in the amino acid deprived condition. Although Chromatin Immunoprecipitation assays showed increased RNA Polymerase II binding at the DKK1 promoter in amino acid-limited conditions, ATF4 binding to the promoter is absent. Luciferase reporter assays did not detect any functional AARE within the DKK1 gene structure. Knockdown of ATF4 by siRNA did not affect the increase of DKK1 mRNA during amino acid limitation. Inhibition of ERK phosphorylation abolished the induction of DKK1. Our study revealed that DKK1 is a novel target gene in the response to amino acid deficiency and that the expression of DKK1 is up-regulated through an ATF4-independent and an ERK-dependent pathway.
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影响因子：
14.9
作者：
Sandoval, J;Rodríguez, JL;López-Rodas, G
通讯作者：
López-Rodas, G
影响因子：
64.8
作者：
NUSSE, R;VANOOYEN, A;VARMUS, H
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VARMUS, H
影响因子：
4.8
作者：
Thiaville, Michelle M.;Pan, Yuan-Xiang;Kilberg, Michael S.
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Kilberg, Michael S.
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Gonzálex-Sancho, JM;Aguilera, O;Muñoz, A
通讯作者：
Muñoz, A
影响因子：
4.8
作者：
Siu, F;Bain, PJ;Kilberg, MS
通讯作者：
Kilberg, MS