The Experts below are selected from a list of 71475 Experts worldwide ranked by ideXlab platform
John D Haley - One of the best experts on this subject based on the ideXlab platform.
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loss of homotypic cell adhesion by epithelial mesenchymal transition or mutation limits sensitivity to epidermal growth factor receptor inhibition
Molecular Cancer Therapeutics, 2007Co-Authors: Elizabeth Buck, Alexandra Eyzaguirre, Sharon Barr, Stuart Thompson, Regina Sennello, David Young, Kenneth K Iwata, Neil W Gibson, Pablo Cagnoni, John D HaleyAbstract:Overexpression and enhanced activation of the epidermal growth factor receptor (EGFR) is frequently observed in human carcinomas. Inhibitors of EGFR signaling have shown clinical utility; however, understanding response at the molecular level is important to define patient subsets most likely to benefit, as well as to support the rational design of drug combinations. Pancreatic and Colorectal Tumor cell lines insensitive to EGFR inhibition were those that had lost or mutated the epithelial junction constituents E-cadherin and γ-catenin, had lost homotypic adhesion, and often gained proteins associated with an epithelial to mesenchymal–like transition, such as vimentin, zeb1, or snail. In matched pairs of Colorectal Tumor cells, the epithelial lines showed an average 7-fold greater sensitivity than mesenchymal-like lines. In human pancreatic and Colorectal Tumor tissues, gain of mesenchymal characteristics and loss of epithelial characteristics correlated with advancing Tumor stage. These data indicate an especially sensitive patient subset as well as a rationale for the combination of EGFR antagonists with agents that affect the epithelial to mesenchymal–like transition process as a mechanism to enhance sensitivity for more advanced mesenchymal-like Tumors. [Mol Cancer Ther 2007;6(2):532–41]
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loss of homotypic cell adhesion by epithelial mesenchymal transition or mutation limits sensitivity to epidermal growth factor receptor inhibition
Molecular Cancer Therapeutics, 2007Co-Authors: Elizabeth Buck, Alexandra Eyzaguirre, Sharon Barr, Stuart Thompson, Regina Sennello, David Young, Kenneth K Iwata, Neil W Gibson, Pablo Cagnoni, John D HaleyAbstract:Overexpression and enhanced activation of the epidermal growth factor receptor (EGFR) is frequently observed in human carcinomas. Inhibitors of EGFR signaling have shown clinical utility; however, understanding response at the molecular level is important to define patient subsets most likely to benefit, as well as to support the rational design of drug combinations. Pancreatic and Colorectal Tumor cell lines insensitive to EGFR inhibition were those that had lost or mutated the epithelial junction constituents E-cadherin and gamma-catenin, had lost homotypic adhesion, and often gained proteins associated with an epithelial to mesenchymal-like transition, such as vimentin, zeb1, or snail. In matched pairs of Colorectal Tumor cells, the epithelial lines showed an average 7-fold greater sensitivity than mesenchymal-like lines. In human pancreatic and Colorectal Tumor tissues, gain of mesenchymal characteristics and loss of epithelial characteristics correlated with advancing Tumor stage. These data indicate an especially sensitive patient subset as well as a rationale for the combination of EGFR antagonists with agents that affect the epithelial to mesenchymal-like transition process as a mechanism to enhance sensitivity for more advanced mesenchymal-like Tumors.
Satoru Kuhara - One of the best experts on this subject based on the ideXlab platform.
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identification of bmp and activin membrane bound inhibitor bambi an inhibitor of transforming growth factor beta signaling as a target of the beta catenin pathway in Colorectal Tumor cells
Journal of Biological Chemistry, 2004Co-Authors: Takashi Sekiya, Shungo Adachi, Kazuyoshi Kohu, Tatsuya Yamada, Osamu Higuchi, Yoichi Furukawa, Yusuke Nakamura, Tsutomu Nakamura, Kousuke Tashiro, Satoru KuharaAbstract:Abstract The Wnt signaling pathway is activated in most human Colorectal Tumors. Mutational inactivation in the Tumor suppressor adenomatous polyposis coli (APC), as well as activation of β-catenin, causes the accumulation of β-catenin, which in turn associates with the T cell factor/lymphoid enhancer factor (TCF/LEF) family of transcription factors and activates transcription of their target genes. Here we show that β-catenin activates transcription of the BMP and activin membrane-bound inhibitor (BAMBI)/NMA gene. The expression level of BAMBI was found to be aberrantly elevated in most Colorectal and hepatocellular carcinomas relative to the corresponding non-cancerous tissues. Expression of BAMBI in Colorectal Tumor cell lines was repressed by a dominant-negative mutant of TCF-4 or by an inhibitor of β-catenin-TCF interaction, suggesting that β-catenin is responsible for the aberrant expression of BAMBI in Colorectal Tumor cells. Furthermore, overexpression of BAMBI inhibited the response of Tumor cells to transforming growth factor-β signaling. These results suggest that β-catenin interferes with transforming growth factor-β-mediated growth arrest by inducing the expression of BAMBI, and this may contribute to Colorectal and hepatocellular Tumorigenesis.
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identification of bmp and activin membrane bound inhibitor bambi an inhibitor of transforming growth factor β signaling as a target of the β catenin pathway in Colorectal Tumor cells
Journal of Biological Chemistry, 2004Co-Authors: Takashi Sekiya, Shungo Adachi, Kazuyoshi Kohu, Tatsuya Yamada, Osamu Higuchi, Yoichi Furukawa, Yusuke Nakamura, Tsutomu Nakamura, Kousuke Tashiro, Satoru KuharaAbstract:The Wnt signaling pathway is activated in most human Colorectal Tumors. Mutational inactivation in the Tumor suppressor adenomatous polyposis coli (APC), as well as activation of β-catenin, causes the accumulation of β-catenin, which in turn associates with the T cell factor/lymphoid enhancer factor (TCF/LEF) family of transcription factors and activates transcription of their target genes. Here we show that β-catenin activates transcription of the BMP and activin membrane-bound inhibitor (BAMBI)/NMA gene. The expression level of BAMBI was found to be aberrantly elevated in most Colorectal and hepatocellular carcinomas relative to the corresponding non-cancerous tissues. Expression of BAMBI in Colorectal Tumor cell lines was repressed by a dominant-negative mutant of TCF-4 or by an inhibitor of β-catenin-TCF interaction, suggesting that β-catenin is responsible for the aberrant expression of BAMBI in Colorectal Tumor cells. Furthermore, overexpression of BAMBI inhibited the response of Tumor cells to transforming growth factor-β signaling. These results suggest that β-catenin interferes with transforming growth factor-β-mediated growth arrest by inducing the expression of BAMBI, and this may contribute to Colorectal and hepatocellular Tumorigenesis.
Elizabeth Buck - One of the best experts on this subject based on the ideXlab platform.
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loss of homotypic cell adhesion by epithelial mesenchymal transition or mutation limits sensitivity to epidermal growth factor receptor inhibition
Molecular Cancer Therapeutics, 2007Co-Authors: Elizabeth Buck, Alexandra Eyzaguirre, Sharon Barr, Stuart Thompson, Regina Sennello, David Young, Kenneth K Iwata, Neil W Gibson, Pablo Cagnoni, John D HaleyAbstract:Overexpression and enhanced activation of the epidermal growth factor receptor (EGFR) is frequently observed in human carcinomas. Inhibitors of EGFR signaling have shown clinical utility; however, understanding response at the molecular level is important to define patient subsets most likely to benefit, as well as to support the rational design of drug combinations. Pancreatic and Colorectal Tumor cell lines insensitive to EGFR inhibition were those that had lost or mutated the epithelial junction constituents E-cadherin and γ-catenin, had lost homotypic adhesion, and often gained proteins associated with an epithelial to mesenchymal–like transition, such as vimentin, zeb1, or snail. In matched pairs of Colorectal Tumor cells, the epithelial lines showed an average 7-fold greater sensitivity than mesenchymal-like lines. In human pancreatic and Colorectal Tumor tissues, gain of mesenchymal characteristics and loss of epithelial characteristics correlated with advancing Tumor stage. These data indicate an especially sensitive patient subset as well as a rationale for the combination of EGFR antagonists with agents that affect the epithelial to mesenchymal–like transition process as a mechanism to enhance sensitivity for more advanced mesenchymal-like Tumors. [Mol Cancer Ther 2007;6(2):532–41]
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loss of homotypic cell adhesion by epithelial mesenchymal transition or mutation limits sensitivity to epidermal growth factor receptor inhibition
Molecular Cancer Therapeutics, 2007Co-Authors: Elizabeth Buck, Alexandra Eyzaguirre, Sharon Barr, Stuart Thompson, Regina Sennello, David Young, Kenneth K Iwata, Neil W Gibson, Pablo Cagnoni, John D HaleyAbstract:Overexpression and enhanced activation of the epidermal growth factor receptor (EGFR) is frequently observed in human carcinomas. Inhibitors of EGFR signaling have shown clinical utility; however, understanding response at the molecular level is important to define patient subsets most likely to benefit, as well as to support the rational design of drug combinations. Pancreatic and Colorectal Tumor cell lines insensitive to EGFR inhibition were those that had lost or mutated the epithelial junction constituents E-cadherin and gamma-catenin, had lost homotypic adhesion, and often gained proteins associated with an epithelial to mesenchymal-like transition, such as vimentin, zeb1, or snail. In matched pairs of Colorectal Tumor cells, the epithelial lines showed an average 7-fold greater sensitivity than mesenchymal-like lines. In human pancreatic and Colorectal Tumor tissues, gain of mesenchymal characteristics and loss of epithelial characteristics correlated with advancing Tumor stage. These data indicate an especially sensitive patient subset as well as a rationale for the combination of EGFR antagonists with agents that affect the epithelial to mesenchymal-like transition process as a mechanism to enhance sensitivity for more advanced mesenchymal-like Tumors.
Yoichi Furukawa - One of the best experts on this subject based on the ideXlab platform.
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xedar as a putative Colorectal Tumor suppressor that mediates p53 regulated anoikis pathway
Oncogene, 2009Co-Authors: Chizu Tanikawa, Yoichi Furukawa, Yusuke Nakamura, Nobuaki Yoshida, Hirofumi Arakawa, Koichi MatsudaAbstract:Colorectal cancers with mutations in the p53 gene have an invasive property, but its underlying mechanism is not fully understood. Through the screening of two data sets of the genome-wide expression profile, one for p53-introduced cells and the other for the numbers of cancer tissues, we report here X-linked ectodermal dysplasia receptor (XEDAR), a member of the TNFR superfamily, as a novel p53 target that has a crucial role in Colorectal carcinogenesis. p53 upregulated XEDAR expression through two p53-binding sites within intron 1 of the XEDAR gene. We also found a significant correlation between decreased XEDAR expressions and p53 gene mutations in breast and lung cancer cell lines (P=0.0043 and P=0.0122, respectively). Furthermore, promoter hypermethylation of the XEDAR gene was detected in 20 of 20 Colorectal cancer cell lines (100%) and in 6 of 12 Colorectal cancer tissues (50%), respectively. Thus, the XEDAR expression was suppressed to <25% of surrounding normal tissues in 12 of 18 Colorectal cancer tissues (66.7%) due to either its epigenetic alterations and/or p53 mutations. We also found that XEDAR interacted with and subsequently caused the accumulation of FAS protein, another member of p53-inducible TNFR. Moreover, XEDAR negatively regulated FAK, a central component of focal adhesion. As a result, inactivation of XEDAR resulted in the enhancement of cell adhesion and spreading, as well as resistance to p53-induced apoptosis. Taken together, our findings showed that XEDAR is a putative Tumor suppressor that could prevent malignant transformation and Tumor progression by regulating apoptosis and anoikis.
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identification of bmp and activin membrane bound inhibitor bambi an inhibitor of transforming growth factor beta signaling as a target of the beta catenin pathway in Colorectal Tumor cells
Journal of Biological Chemistry, 2004Co-Authors: Takashi Sekiya, Shungo Adachi, Kazuyoshi Kohu, Tatsuya Yamada, Osamu Higuchi, Yoichi Furukawa, Yusuke Nakamura, Tsutomu Nakamura, Kousuke Tashiro, Satoru KuharaAbstract:Abstract The Wnt signaling pathway is activated in most human Colorectal Tumors. Mutational inactivation in the Tumor suppressor adenomatous polyposis coli (APC), as well as activation of β-catenin, causes the accumulation of β-catenin, which in turn associates with the T cell factor/lymphoid enhancer factor (TCF/LEF) family of transcription factors and activates transcription of their target genes. Here we show that β-catenin activates transcription of the BMP and activin membrane-bound inhibitor (BAMBI)/NMA gene. The expression level of BAMBI was found to be aberrantly elevated in most Colorectal and hepatocellular carcinomas relative to the corresponding non-cancerous tissues. Expression of BAMBI in Colorectal Tumor cell lines was repressed by a dominant-negative mutant of TCF-4 or by an inhibitor of β-catenin-TCF interaction, suggesting that β-catenin is responsible for the aberrant expression of BAMBI in Colorectal Tumor cells. Furthermore, overexpression of BAMBI inhibited the response of Tumor cells to transforming growth factor-β signaling. These results suggest that β-catenin interferes with transforming growth factor-β-mediated growth arrest by inducing the expression of BAMBI, and this may contribute to Colorectal and hepatocellular Tumorigenesis.
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identification of bmp and activin membrane bound inhibitor bambi an inhibitor of transforming growth factor β signaling as a target of the β catenin pathway in Colorectal Tumor cells
Journal of Biological Chemistry, 2004Co-Authors: Takashi Sekiya, Shungo Adachi, Kazuyoshi Kohu, Tatsuya Yamada, Osamu Higuchi, Yoichi Furukawa, Yusuke Nakamura, Tsutomu Nakamura, Kousuke Tashiro, Satoru KuharaAbstract:The Wnt signaling pathway is activated in most human Colorectal Tumors. Mutational inactivation in the Tumor suppressor adenomatous polyposis coli (APC), as well as activation of β-catenin, causes the accumulation of β-catenin, which in turn associates with the T cell factor/lymphoid enhancer factor (TCF/LEF) family of transcription factors and activates transcription of their target genes. Here we show that β-catenin activates transcription of the BMP and activin membrane-bound inhibitor (BAMBI)/NMA gene. The expression level of BAMBI was found to be aberrantly elevated in most Colorectal and hepatocellular carcinomas relative to the corresponding non-cancerous tissues. Expression of BAMBI in Colorectal Tumor cell lines was repressed by a dominant-negative mutant of TCF-4 or by an inhibitor of β-catenin-TCF interaction, suggesting that β-catenin is responsible for the aberrant expression of BAMBI in Colorectal Tumor cells. Furthermore, overexpression of BAMBI inhibited the response of Tumor cells to transforming growth factor-β signaling. These results suggest that β-catenin interferes with transforming growth factor-β-mediated growth arrest by inducing the expression of BAMBI, and this may contribute to Colorectal and hepatocellular Tumorigenesis.
Yusuke Nakamura - One of the best experts on this subject based on the ideXlab platform.
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xedar as a putative Colorectal Tumor suppressor that mediates p53 regulated anoikis pathway
Oncogene, 2009Co-Authors: Chizu Tanikawa, Yoichi Furukawa, Yusuke Nakamura, Nobuaki Yoshida, Hirofumi Arakawa, Koichi MatsudaAbstract:Colorectal cancers with mutations in the p53 gene have an invasive property, but its underlying mechanism is not fully understood. Through the screening of two data sets of the genome-wide expression profile, one for p53-introduced cells and the other for the numbers of cancer tissues, we report here X-linked ectodermal dysplasia receptor (XEDAR), a member of the TNFR superfamily, as a novel p53 target that has a crucial role in Colorectal carcinogenesis. p53 upregulated XEDAR expression through two p53-binding sites within intron 1 of the XEDAR gene. We also found a significant correlation between decreased XEDAR expressions and p53 gene mutations in breast and lung cancer cell lines (P=0.0043 and P=0.0122, respectively). Furthermore, promoter hypermethylation of the XEDAR gene was detected in 20 of 20 Colorectal cancer cell lines (100%) and in 6 of 12 Colorectal cancer tissues (50%), respectively. Thus, the XEDAR expression was suppressed to <25% of surrounding normal tissues in 12 of 18 Colorectal cancer tissues (66.7%) due to either its epigenetic alterations and/or p53 mutations. We also found that XEDAR interacted with and subsequently caused the accumulation of FAS protein, another member of p53-inducible TNFR. Moreover, XEDAR negatively regulated FAK, a central component of focal adhesion. As a result, inactivation of XEDAR resulted in the enhancement of cell adhesion and spreading, as well as resistance to p53-induced apoptosis. Taken together, our findings showed that XEDAR is a putative Tumor suppressor that could prevent malignant transformation and Tumor progression by regulating apoptosis and anoikis.
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identification of bmp and activin membrane bound inhibitor bambi an inhibitor of transforming growth factor beta signaling as a target of the beta catenin pathway in Colorectal Tumor cells
Journal of Biological Chemistry, 2004Co-Authors: Takashi Sekiya, Shungo Adachi, Kazuyoshi Kohu, Tatsuya Yamada, Osamu Higuchi, Yoichi Furukawa, Yusuke Nakamura, Tsutomu Nakamura, Kousuke Tashiro, Satoru KuharaAbstract:Abstract The Wnt signaling pathway is activated in most human Colorectal Tumors. Mutational inactivation in the Tumor suppressor adenomatous polyposis coli (APC), as well as activation of β-catenin, causes the accumulation of β-catenin, which in turn associates with the T cell factor/lymphoid enhancer factor (TCF/LEF) family of transcription factors and activates transcription of their target genes. Here we show that β-catenin activates transcription of the BMP and activin membrane-bound inhibitor (BAMBI)/NMA gene. The expression level of BAMBI was found to be aberrantly elevated in most Colorectal and hepatocellular carcinomas relative to the corresponding non-cancerous tissues. Expression of BAMBI in Colorectal Tumor cell lines was repressed by a dominant-negative mutant of TCF-4 or by an inhibitor of β-catenin-TCF interaction, suggesting that β-catenin is responsible for the aberrant expression of BAMBI in Colorectal Tumor cells. Furthermore, overexpression of BAMBI inhibited the response of Tumor cells to transforming growth factor-β signaling. These results suggest that β-catenin interferes with transforming growth factor-β-mediated growth arrest by inducing the expression of BAMBI, and this may contribute to Colorectal and hepatocellular Tumorigenesis.
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identification of bmp and activin membrane bound inhibitor bambi an inhibitor of transforming growth factor β signaling as a target of the β catenin pathway in Colorectal Tumor cells
Journal of Biological Chemistry, 2004Co-Authors: Takashi Sekiya, Shungo Adachi, Kazuyoshi Kohu, Tatsuya Yamada, Osamu Higuchi, Yoichi Furukawa, Yusuke Nakamura, Tsutomu Nakamura, Kousuke Tashiro, Satoru KuharaAbstract:The Wnt signaling pathway is activated in most human Colorectal Tumors. Mutational inactivation in the Tumor suppressor adenomatous polyposis coli (APC), as well as activation of β-catenin, causes the accumulation of β-catenin, which in turn associates with the T cell factor/lymphoid enhancer factor (TCF/LEF) family of transcription factors and activates transcription of their target genes. Here we show that β-catenin activates transcription of the BMP and activin membrane-bound inhibitor (BAMBI)/NMA gene. The expression level of BAMBI was found to be aberrantly elevated in most Colorectal and hepatocellular carcinomas relative to the corresponding non-cancerous tissues. Expression of BAMBI in Colorectal Tumor cell lines was repressed by a dominant-negative mutant of TCF-4 or by an inhibitor of β-catenin-TCF interaction, suggesting that β-catenin is responsible for the aberrant expression of BAMBI in Colorectal Tumor cells. Furthermore, overexpression of BAMBI inhibited the response of Tumor cells to transforming growth factor-β signaling. These results suggest that β-catenin interferes with transforming growth factor-β-mediated growth arrest by inducing the expression of BAMBI, and this may contribute to Colorectal and hepatocellular Tumorigenesis.