Receptor and secreted targets of Wnt-1/beta-catenin signalling in mouse mammary epithelial cells.
Receptor and secreted targets of Wnt-1/beta-catenin signalling in mouse mammary epithelial cells.
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DOI：
10.1186/1471-2407-5-3
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发表时间：
2005-01-10
期刊：
影响因子：
3.8
通讯作者：
Ashworth A
中科院分区：
文献类型：
--
作者：
Kenny PA;Enver T;Ashworth A
Wnt/ β-连环蛋白信号转导通路的失调与乳腺、结肠和其他组织中肿瘤的发病机制有关。该途径组分的突变导致β-连环蛋白稳定和积累，以及β-连环蛋白/TCF靶基因的异常调节。细胞转录谱的这种改变被认为是这些癌症发病机制的基础。我们试图在小鼠乳腺上皮细胞中鉴定该途径的新靶基因。基因表达微阵列分析小鼠乳腺上皮细胞诱导表达的组成型活性突变的β-连环蛋白被用来确定该途径的靶基因。通过北方印迹法分别验证了Autotaxin、细胞外基质蛋白1（ECm 1）、CD 14、缺氧诱导基因2（Hig 2）和受体活性修饰蛋白3（RAMP 3）等5个推定靶基因对ΔNβ-catenin应答的差异表达。这些基因中的每一个编码受体或分泌蛋白，其调节可能是Wnt/β-连环蛋白肿瘤细胞之间以及肿瘤与其微环境之间相互作用的基础。这些基因之一，Hig 2，先前显示在人宫颈癌细胞中由缺氧和葡萄糖剥夺诱导，在ΔNβ-连环蛋白诱导后被强烈抑制。Hig 2的N-末端含有一个推测的信号肽，表明它可能是分泌的。与此一致，Hig 2-EGFP融合蛋白能够进入分泌途径，并在条件培养基中检测到。在假定的信号序列中的关键残基的突变废除了它的分泌。在一组人肿瘤中检查了人HIGH 2的表达，发现与正常相邻组织相比，在肾肿瘤中人HIGH 2的表达显著下调。HIGH 2代表了Wnt通路的一种新的非细胞自主靶点，其可能参与人类癌症。
Deregulation of the Wnt/ β-catenin signal transduction pathway has been implicated in the pathogenesis of tumours in the mammary gland, colon and other tissues. Mutations in components of this pathway result in β-catenin stabilization and accumulation, and the aberrant modulation of β-catenin/TCF target genes. Such alterations in the cellular transcriptional profile are believed to underlie the pathogenesis of these cancers. We have sought to identify novel target genes of this pathway in mouse mammary epithelial cells. Gene expression microarray analysis of mouse mammary epithelial cells inducibly expressing a constitutively active mutant of β-catenin was used to identify target genes of this pathway. The differential expression in response to ΔNβ-catenin for five putative target genes, Autotaxin, Extracellular Matrix Protein 1 (Ecm1), CD14, Hypoxia-inducible gene 2 (Hig2) and Receptor Activity Modifying Protein 3 (RAMP3), was independently validated by northern blotting. Each of these genes encodes either a receptor or a secreted protein, modulation of which may underlie the interactions between Wnt/β-catenin tumour cells and between the tumour and its microenvironment. One of these genes, Hig2, previously shown to be induced by both hypoxia and glucose deprivation in human cervical carcinoma cells, was strongly repressed upon ΔNβ-catenin induction. The predicted N-terminus of Hig2 contains a putative signal peptide suggesting it might be secreted. Consistent with this, a Hig2-EGFP fusion protein was able to enter the secretory pathway and was detected in conditioned medium. Mutation of critical residues in the putative signal sequence abolished its secretion. The expression of human HIG2 was examined in a panel of human tumours and was found to be significantly downregulated in kidney tumours compared to normal adjacent tissue. HIG2 represents a novel non-cell autonomous target of the Wnt pathway which is potentially involved in human cancer.
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影响因子：
64.5
作者：
GRODEN, J;THLIVERIS, A;WHITE, R
通讯作者：
WHITE, R
DOI：
10.1073/pnas.96.4.1603
发表时间：
1999-02-16
影响因子：
11.1
作者：
Mann, B;Gelos, M;Hanski, C
通讯作者：
Hanski, C
DOI：
10.1084/jem.191.10.1807
发表时间：
2000-05-15
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Labéta MO;Vidal K;Nores JE;Arias M;Vita N;Morgan BP;Guillemot JC;Loyaux D;Ferrara P;Schmid D;Affolter M;Borysiewicz LK;Donnet-Hughes A;Schiffrin EJ
通讯作者：
Schiffrin EJ
影响因子：
56.9
作者：
He, TC;Sparks, AB;Kinzler, KW
通讯作者：
Kinzler, KW
影响因子：
11.4
作者：
Aberle, H;Bauer, A;Kemler, R
通讯作者：
Kemler, R