| Evi1 is a survival factor which conveys resistance to both TGFbeta- and taxol-mediated cell death via PI3K/AKT. | |
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MedLine Citation:
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PMID: 16462766 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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In hematopoietic cells the transforming potential of the ecotropic viral integration site 1 (Evi1) oncogene is thought to be dependent upon the ability to inhibit TGFbeta signaling. Although Evi1 has recently been implicated in certain epithelial cancers, the effects of Evi1 on transformation and TGFbeta signaling in epithelial cells are not completely understood. Herein, we have determined the effects of Evi1 on TGFbeta signaling in intestinal epithelial cells. Stable expression of Evi1 in non-transformed intestinal epithelial cells inhibited induction of some Smad3-dependent TGFbeta target genes, such as PAI1. However, TGFbeta-mediated induction of cellular adhesion signaling components such as integrin1 and paxillin was not inhibited by Evi1; nor did Evi1 inhibit TGFbeta-mediated epithelial to mesenchymal transition. Likewise, Evi1 did not inhibit TGFbeta-mediated downregulation of cyclin D1 or block TGFbeta-mediated growth inhibition. However, Evi1 did inhibit TGFbeta-mediated apoptosis by a process that involves phosphoinositide-3-kinase (PI3K) and its downstream effector AKT. The ability of Evi1 to suppress apoptosis is not restricted to TGFbeta-mediated cell death, since Evi1 also protects intestinal epithelial cells from taxol-mediated apoptosis. Evi1 is overexpressed in some human colon cancer cell lines, and overexpression is associated with amplification of the Evi1 gene. Knockdown of Evi1 by siRNA inhibited AKT phosphorylation in HT-29 human colon cancer cells and increased their sensitivity to taxol-mediated apoptosis. These data indicate that Evi1 functions as a survival gene in intestinal epithelial cells and colon cancer cells, activating PI3K/AKT and conveying resistance to both physiological and therapeutic apoptotic stimuli. |
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Authors:
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Y Liu; L Chen; T C Ko; A P Fields; E A Thompson |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2006-02-06 |
Journal Detail:
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Title: Oncogene Volume: 25 ISSN: 0950-9232 ISO Abbreviation: Oncogene Publication Date: 2006 Jun |
Date Detail:
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Created Date: 2006-06-15 Completed Date: 2006-08-03 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 8711562 Medline TA: Oncogene Country: England |
Other Details:
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Languages: eng Pagination: 3565-75 Citation Subset: IM |
Affiliation:
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Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Jacksonville, FL 32224, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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1-Phosphatidylinositol 3-Kinase
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metabolism* Animals Antineoplastic Agents, Phytogenic / pharmacology* Apoptosis / physiology Cell Line, Tumor Cell Movement / physiology Colonic Neoplasms / metabolism DNA-Binding Proteins / metabolism* Drug Resistance, Neoplasm / physiology* Humans Intestinal Mucosa / metabolism Oncogene Protein v-akt / metabolism* Paclitaxel / pharmacology* Proto-Oncogenes / physiology* Rats Signal Transduction / physiology Transcription Factors / metabolism* Transcriptional Activation Transforming Growth Factor beta / metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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P01DK35608/DK/NIDDK NIH HHS; R01CA64701/CA/NCI NIH HHS; R01DK060105/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antineoplastic Agents, Phytogenic; 0/DNA-Binding Proteins; 0/Transcription Factors; 0/Transforming Growth Factor beta; 33069-62-4/Paclitaxel; EC 2.7.1.137/1-Phosphatidylinositol 3-Kinase; EC 2.7.11.1/Oncogene Protein v-akt |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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