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Molecular mechanism of involvement of homeobox transcription factors Cdx2 and Cdxl in intestinal tumors

同源框转录因子Cdx2和Cdxl参与肠道肿瘤的分子机制

基本信息

批准号：
17390113
负责人：
AOKI Masahiro
金额：
$ 10.16万
依托单位：
Kyoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2007
项目状态：
已结题

项目摘要

The caudal-type homeobox transcription factors Cdx2 and Cdx1 ate involved in differentiation and tumorigenesis of intestinal epthelial cells, yet the underlying molecular mechanisms remain unclear. In this study, we have identified SLC5A8 and PLEKHG1 as novel target genes of Cdx2 and Cdx1, by using an improved version of chromatin immunoprecipitation (ChIP) screen. SLC5A8 codes for a sodium-coupled transporter for short chain fatty adds and monocarboxylates, including butyrate and pyruvate. Expression of SLC5A8 is frequently down regulated in colon cancer, and higher expression of SLC5A8 correlates with longer disease-free survival in colon cancer patients. Reporter gene assays using SLC5A8 promoter and qRT-PCR analysis of SLC5A8 in human colon cancer cell fines following forced expression or knockdown of CDX2 and/or CDX1 have shown that SLC5A8 is indeed a direct transcriptional target of Cdx2 and Cdx1. On the other hand, PLEKHG1 encodes a protein with 1385 amino acids, carrying Dbl-homology (DH) domain and pleckstrin homology (PH) domain. Although ft is expected to function as a GTP/GDP exchange factor (GEF) for Rho/Rac/Cdc42 family small G-proteins, no reports have been published of this molecule. We have found that PLEKHG1 is expressed in the normal intestinal tissues as well as in a subset of colon cancer cell lines, and that its expression is regulated by CDX2 and CDX1. Further characterization of these novel target genes of Cdx is expected to reveal their roles in differentiation and/or tumorigenesis of the intestinal epithelial cells. We have also shown that PKC ζ, an atypical PKC involved in cell polarity control, can phosphorylate a well-conserved threonine reside in the homeodomain of Cdx2, and that phosphorylation of this residue may regulate dimerization of Cdx2. Further analysis of the possible link between PKC signaling and Cdx2 may he understand the mechanism by which Cdx2 controls their differentiation and transformation.

尾型同源异型盒转录因子Cdx 2和Cdx 1参与肠上皮细胞的分化和肿瘤发生，但其分子机制尚不清楚。在这项研究中，我们已经确定了SLC 5A 8和PLEKHG 1作为新的靶基因的Cdx 2和Cdx 1，通过使用改进版本的染色质免疫沉淀（ChIP）屏幕。SLC 5A 8编码短链脂肪酸和单羧酸盐（包括丁酸盐和丙酮酸盐）的钠偶联转运蛋白。SLC 5A 8的表达在结肠癌中经常下调，并且SLC 5A 8的较高表达与结肠癌患者的较长无病生存期相关。使用SLC 5A 8启动子的报告基因测定和在CDX 2和/或CDX 1的强制表达或敲低后的人结肠癌细胞细颗粒中SLC 5A 8的qRT-PCR分析已经表明，SLC 5A 8确实是Cdx 2和Cdx 1的直接转录靶标。另一方面，PLEKHG 1编码一个1385个氨基酸的蛋白质，带有Dbl-homology（DH）结构域和pleckstrin homology（PH）结构域。虽然FT预期作为Rho/Rac/Cdc 42家族小G蛋白的GTP/GDP交换因子（GEF）起作用，但尚未发表该分子的报道。我们已经发现PLEKHG 1在正常肠组织中以及在结肠癌细胞系的子集中表达，并且其表达受CDX 2和CDX 1调节。这些新的Cdx靶基因的进一步表征有望揭示它们在肠上皮细胞分化和/或肿瘤发生中的作用。我们还表明，PKC β，一个非典型的PKC参与细胞极性控制，可以磷酸化一个保守的苏氨酸驻留在Cdx 2的同源结构域，这个残基的磷酸化可以调节Cdx 2的二聚化。进一步分析PKC信号通路与Cdx 2之间的可能联系，有助于了解Cdx 2调控细胞分化和转化的机制。

项目成果

期刊论文数量（0）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Suppression of tubulin polymerization by the LKB1-MARK signaling.

LKB1-MARK 信号传导抑制微管蛋白聚合。

DOI：
发表时间：
2007
期刊：
影响因子：
0
作者：
Aoki;K. et al.;小島康
通讯作者：
小島康

Chromosomal instability by beta-catenin/TCF transcription in APC or beta-catenin mutant cells.

DOI：
发表时间：
2007
期刊：
Oncogene
影响因子：
8
作者：
K. Aoki;M. Aoki;M. Sugai;N. Harada;H. Miyoshi;T. Tsukamoto;T. Mizoshita;M. Tatematsu;H. Seno;T. Chiba;M. Oshima;C. Hsieh;M. Taketo
通讯作者：
K. Aoki;M. Aoki;M. Sugai;N. Harada;H. Miyoshi;T. Tsukamoto;T. Mizoshita;M. Tatematsu;H. Seno;T. Chiba;M. Oshima;C. Hsieh;M. Taketo

SMAD4-deficient intestinal tumors recruit CCR1^+-myeloid cells that help invasion.

SMAD4 缺陷的肠道肿瘤会招募有助于侵袭的 CCR1^-骨髓细胞。