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Transforming growth factor-β suppresses nonmetastatic colon cancer through smad4 and adaptor protein ELF at an early stage of tumorigenesis
Although transforming growth factor-beta (TGF-beta) is both a suppressor and promoter of tumorigenesis, its contribution to early tumor suppression and staging remains largely unknown. In search of the mechanism of early tumor suppression, we identified the adaptor protein ELF, a beta-spectrin from...
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| Published in: | Cancer research (Chicago, Ill.) Ill.), 2005-05, Vol.65 (10), p.4228-4237 |
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| container_end_page | 4237 |
| container_issue | 10 |
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| container_title | Cancer research (Chicago, Ill.) |
| container_volume | 65 |
| creator | YI TANG KATUN, Varalakshmi MISHRA, Bibhuti MISHRA, Lopa SRINIVASAN, Radhika FOGT, Franz REDMAN, Robert ANAND, Girish SAID, Anan FISHBEIN, Thomas ZASLOFF, Michael REDDY, E. Premkumar |
| description | Although transforming growth factor-beta (TGF-beta) is both a suppressor and promoter of tumorigenesis, its contribution to early tumor suppression and staging remains largely unknown. In search of the mechanism of early tumor suppression, we identified the adaptor protein ELF, a beta-spectrin from stem/progenitor cells committed to foregut lineage. ELF activates and modulates Smad4 activation of TGF-beta to confer cell polarity, to maintain cell architecture, and to inhibit epithelial-to-mesenchymal transition. Analysis of development of colon cancer in (adult) elf+/-/Smad4+/-, elf+/-, Smad4+/-, and gut epithelial cells from elf-/- mutant mouse embryos pinpoints the defect to hyperplasia/adenoma transition. Further analysis of the role of ELF in human colorectal cancer confirms reduced expression of ELF in Dukes' B1 stage tissues (P < 0.05) and of Smad4 in advanced colon cancers (P < 0.05). This study indicates that by modulating Smad 4, ELF has a key role in TGF-beta signaling in the suppression of early colon cancer. |
| doi_str_mv | 10.1158/0008-5472.CAN-04-4585 |
| format | article |
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Premkumar</creator><creatorcontrib>YI TANG ; KATUN, Varalakshmi ; MISHRA, Bibhuti ; MISHRA, Lopa ; SRINIVASAN, Radhika ; FOGT, Franz ; REDMAN, Robert ; ANAND, Girish ; SAID, Anan ; FISHBEIN, Thomas ; ZASLOFF, Michael ; REDDY, E. Premkumar</creatorcontrib><description>Although transforming growth factor-beta (TGF-beta) is both a suppressor and promoter of tumorigenesis, its contribution to early tumor suppression and staging remains largely unknown. In search of the mechanism of early tumor suppression, we identified the adaptor protein ELF, a beta-spectrin from stem/progenitor cells committed to foregut lineage. ELF activates and modulates Smad4 activation of TGF-beta to confer cell polarity, to maintain cell architecture, and to inhibit epithelial-to-mesenchymal transition. Analysis of development of colon cancer in (adult) elf+/-/Smad4+/-, elf+/-, Smad4+/-, and gut epithelial cells from elf-/- mutant mouse embryos pinpoints the defect to hyperplasia/adenoma transition. Further analysis of the role of ELF in human colorectal cancer confirms reduced expression of ELF in Dukes' B1 stage tissues (P < 0.05) and of Smad4 in advanced colon cancers (P < 0.05). This study indicates that by modulating Smad 4, ELF has a key role in TGF-beta signaling in the suppression of early colon cancer.</description><identifier>ISSN: 0008-5472</identifier><identifier>EISSN: 1538-7445</identifier><identifier>DOI: 10.1158/0008-5472.CAN-04-4585</identifier><identifier>PMID: 15899814</identifier><identifier>CODEN: CNREA8</identifier><language>eng</language><publisher>Philadelphia, PA: American Association for Cancer Research</publisher><subject>Animals ; Antineoplastic agents ; Apoptosis - physiology ; Biological and medical sciences ; Cell Growth Processes - physiology ; Colonic Neoplasms - genetics ; Colonic Neoplasms - metabolism ; Colonic Neoplasms - pathology ; DNA-Binding Proteins - genetics ; DNA-Binding Proteins - metabolism ; Gastroenterology. Liver. Pancreas. 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Premkumar</creatorcontrib><title>Transforming growth factor-β suppresses nonmetastatic colon cancer through smad4 and adaptor protein ELF at an early stage of tumorigenesis</title><title>Cancer research (Chicago, Ill.)</title><addtitle>Cancer Res</addtitle><description>Although transforming growth factor-beta (TGF-beta) is both a suppressor and promoter of tumorigenesis, its contribution to early tumor suppression and staging remains largely unknown. In search of the mechanism of early tumor suppression, we identified the adaptor protein ELF, a beta-spectrin from stem/progenitor cells committed to foregut lineage. ELF activates and modulates Smad4 activation of TGF-beta to confer cell polarity, to maintain cell architecture, and to inhibit epithelial-to-mesenchymal transition. Analysis of development of colon cancer in (adult) elf+/-/Smad4+/-, elf+/-, Smad4+/-, and gut epithelial cells from elf-/- mutant mouse embryos pinpoints the defect to hyperplasia/adenoma transition. Further analysis of the role of ELF in human colorectal cancer confirms reduced expression of ELF in Dukes' B1 stage tissues (P < 0.05) and of Smad4 in advanced colon cancers (P < 0.05). This study indicates that by modulating Smad 4, ELF has a key role in TGF-beta signaling in the suppression of early colon cancer.</description><subject>Animals</subject><subject>Antineoplastic agents</subject><subject>Apoptosis - physiology</subject><subject>Biological and medical sciences</subject><subject>Cell Growth Processes - physiology</subject><subject>Colonic Neoplasms - genetics</subject><subject>Colonic Neoplasms - metabolism</subject><subject>Colonic Neoplasms - pathology</subject><subject>DNA-Binding Proteins - genetics</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Gastroenterology. Liver. Pancreas. Abdomen</subject><subject>Humans</subject><subject>Intestinal Mucosa - metabolism</subject><subject>Intestinal Mucosa - pathology</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Pharmacology. Drug treatments</subject><subject>Smad4 Protein</subject><subject>Spectrin - deficiency</subject><subject>Spectrin - genetics</subject><subject>Spectrin - metabolism</subject><subject>Stomach. Duodenum. Small intestine. Colon. Rectum. Anus</subject><subject>Trans-Activators - genetics</subject><subject>Trans-Activators - metabolism</subject><subject>Transforming Growth Factor beta</subject><subject>Tumors</subject><issn>0008-5472</issn><issn>1538-7445</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2005</creationdate><recordtype>article</recordtype><recordid>eNqFkUFO3TAQhq2KqjxojwDyhu5CbWzHzhI9QYv01G7o2nJsJy8osYPHEeIOnKYH6ZnqiCdYdmWN_M0_o_kQOqPkklKhvhFCVCW4vLrcXv-sCK-4UOID2lDBVCU5F0do88YcoxOAh1IKSsQndFwCmkZRvkEv98kE6GKahtDjPsWnvMedsTmm6u8fDMs8Jw_gAYcYJp8NZJMHi20cY8DWBOsTzvsUl36PYTKOYxMcNs7MJQLPKWY_BHyzu8Umly_sTRqfcUnpPY4dzssU09D74GGAz-hjZ0bwXw7vKfp9e3O__VHtfn2_217vKsupyFUjiGplV0t7ZU3LKJHKt5S0TlAmCbfCCV8bV0tqSa2s6IjnrqHOESZq2zB2ir6-5pb1HhcPWU8DWD-OJvi4gK6lYuU-8r8glYwrxldQvII2RYDkOz2nYTLpWVOiV196daFXF7r40oTr1VfpOz8MWNrJu_eug6ACXBwAA9aMXbFlB3jnyqqEMcH-ARf5oTg</recordid><startdate>20050515</startdate><enddate>20050515</enddate><creator>YI TANG</creator><creator>KATUN, Varalakshmi</creator><creator>MISHRA, Bibhuti</creator><creator>MISHRA, Lopa</creator><creator>SRINIVASAN, Radhika</creator><creator>FOGT, Franz</creator><creator>REDMAN, Robert</creator><creator>ANAND, Girish</creator><creator>SAID, Anan</creator><creator>FISHBEIN, Thomas</creator><creator>ZASLOFF, Michael</creator><creator>REDDY, E. 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Premkumar</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Transforming growth factor-β suppresses nonmetastatic colon cancer through smad4 and adaptor protein ELF at an early stage of tumorigenesis</atitle><jtitle>Cancer research (Chicago, Ill.)</jtitle><addtitle>Cancer Res</addtitle><date>2005-05-15</date><risdate>2005</risdate><volume>65</volume><issue>10</issue><spage>4228</spage><epage>4237</epage><pages>4228-4237</pages><issn>0008-5472</issn><eissn>1538-7445</eissn><coden>CNREA8</coden><abstract>Although transforming growth factor-beta (TGF-beta) is both a suppressor and promoter of tumorigenesis, its contribution to early tumor suppression and staging remains largely unknown. In search of the mechanism of early tumor suppression, we identified the adaptor protein ELF, a beta-spectrin from stem/progenitor cells committed to foregut lineage. ELF activates and modulates Smad4 activation of TGF-beta to confer cell polarity, to maintain cell architecture, and to inhibit epithelial-to-mesenchymal transition. Analysis of development of colon cancer in (adult) elf+/-/Smad4+/-, elf+/-, Smad4+/-, and gut epithelial cells from elf-/- mutant mouse embryos pinpoints the defect to hyperplasia/adenoma transition. Further analysis of the role of ELF in human colorectal cancer confirms reduced expression of ELF in Dukes' B1 stage tissues (P < 0.05) and of Smad4 in advanced colon cancers (P < 0.05). This study indicates that by modulating Smad 4, ELF has a key role in TGF-beta signaling in the suppression of early colon cancer.</abstract><cop>Philadelphia, PA</cop><pub>American Association for Cancer Research</pub><pmid>15899814</pmid><doi>10.1158/0008-5472.CAN-04-4585</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Cancer research (Chicago, Ill.), 2005-05, Vol.65 (10), p.4228-4237 |
| issn | 0008-5472 1538-7445 |
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| subjects | Animals Antineoplastic agents Apoptosis - physiology Biological and medical sciences Cell Growth Processes - physiology Colonic Neoplasms - genetics Colonic Neoplasms - metabolism Colonic Neoplasms - pathology DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism Gastroenterology. Liver. Pancreas. Abdomen Humans Intestinal Mucosa - metabolism Intestinal Mucosa - pathology Medical sciences Mice Mice, Knockout Pharmacology. Drug treatments Smad4 Protein Spectrin - deficiency Spectrin - genetics Spectrin - metabolism Stomach. Duodenum. Small intestine. Colon. Rectum. Anus Trans-Activators - genetics Trans-Activators - metabolism Transforming Growth Factor beta Tumors |
| title | Transforming growth factor-β suppresses nonmetastatic colon cancer through smad4 and adaptor protein ELF at an early stage of tumorigenesis |
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