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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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2005-05, Vol.65 (10), p.4228-4237
Main Authors: 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
Format: Article
Language:English
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
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Summary: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.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-04-4585