The Rac Activator Tiam1 Is a Wnt-responsive Gene That Modifies Intestinal Tumor Development
Mutations in the canonical Wnt signaling pathway leading to its activation are known to cause the majority of intestinal tumors. However, few genes targeted by this pathway have been demonstrated to affect tumor development in vivo. Here we show that Tiam1, a selective Rac GTPase activator, is a Wnt...
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| Veröffentlicht in: | The Journal of biological chemistry 2006-01, Vol.281 (1), p.543-548 |
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| container_title | The Journal of biological chemistry |
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| creator | Malliri, Angeliki Rygiel, Tomasz P. van der Kammen, Rob A. Song, Ji-Ying Engers, Rainer Hurlstone, Adam F.L. Clevers, Hans Collard, John G. |
| description | Mutations in the canonical Wnt signaling pathway leading to its activation are known to cause the majority of intestinal tumors. However, few genes targeted by this pathway have been demonstrated to affect tumor development in vivo. Here we show that Tiam1, a selective Rac GTPase activator, is a Wnt-responsive gene expressed in the base of intestinal crypts and up-regulated in mouse intestinal tumors and human colon adenomas. Moreover, by comparing tumor development in APC mutant Min (multiple intestinal neoplasia) mice expressing or lacking Tiam1, we found that Tiam1 deficiency significantly reduces the formation and growth of polyps in vivo. However, invasion of malignant intestinal tumors is enhanced by a lack of Tiam1. In line with this, knock-down of Tiam1 reduced the growth potential of human colorectal cancer cells and their ability to form E-cadherin-based adhesions, a prerequisite for local invasion of tumor cells. Our data indicate a novel cross-talk between Tiam1-Rac and canonical Wnt-signaling pathways that influences intestinal tumor formation and progression. |
| doi_str_mv | 10.1074/jbc.M507582200 |
| format | Article |
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However, few genes targeted by this pathway have been demonstrated to affect tumor development in vivo. Here we show that Tiam1, a selective Rac GTPase activator, is a Wnt-responsive gene expressed in the base of intestinal crypts and up-regulated in mouse intestinal tumors and human colon adenomas. Moreover, by comparing tumor development in APC mutant Min (multiple intestinal neoplasia) mice expressing or lacking Tiam1, we found that Tiam1 deficiency significantly reduces the formation and growth of polyps in vivo. However, invasion of malignant intestinal tumors is enhanced by a lack of Tiam1. In line with this, knock-down of Tiam1 reduced the growth potential of human colorectal cancer cells and their ability to form E-cadherin-based adhesions, a prerequisite for local invasion of tumor cells. 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| subjects | Adenoma - genetics Adenoma - metabolism Adenoma - pathology Animals Cells, Cultured Colorectal Neoplasms - genetics Colorectal Neoplasms - metabolism Colorectal Neoplasms - pathology Gene Expression Regulation, Neoplastic Guanine Nucleotide Exchange Factors - genetics Guanine Nucleotide Exchange Factors - metabolism Mice Mice, Inbred C57BL Mice, Mutant Strains Neoplasm Proteins - genetics Neoplasm Proteins - metabolism rac GTP-Binding Proteins - metabolism Signal Transduction T-Lymphoma Invasion and Metastasis-inducing Protein 1 Transfection Wnt Proteins - metabolism |
| title | The Rac Activator Tiam1 Is a Wnt-responsive Gene That Modifies Intestinal Tumor Development |
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