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Research Article Free access | 10.1172/JCI117987

The neurotensin gene is a downstream target for Ras activation.

B M Evers, Z Zhou, P Celano, and J Li

Department of Surgery, University of Texas Medical Branch, Galveston 77555, USA.

Find articles by Evers, B. in: PubMed | Google Scholar

Department of Surgery, University of Texas Medical Branch, Galveston 77555, USA.

Find articles by Zhou, Z. in: PubMed | Google Scholar

Department of Surgery, University of Texas Medical Branch, Galveston 77555, USA.

Find articles by Celano, P. in: PubMed | Google Scholar

Department of Surgery, University of Texas Medical Branch, Galveston 77555, USA.

Find articles by Li, J. in: PubMed | Google Scholar

Published June 1, 1995 - More info

Published in Volume 95, Issue 6 on June 1, 1995
J Clin Invest. 1995;95(6):2822–2830. https://doi.org/10.1172/JCI117987.
© 1995 The American Society for Clinical Investigation
Published June 1, 1995 - Version history
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Abstract

Ras regulates novel patterns of gene expression and the differentiation of various eukaryotic cell types. Stable transfection of Ha-ras into the human colon cancer line CaCo2 results in the morphologic differentiation to a small bowel phenotype. The purpose of our study was to determine whether the Ras regulatory pathway plays a role in the expression of the neurotensin gene (NT/N), a terminally differentiated endocrine product specifically localized in the gastrointestinal tract to the adult small bowel. We found that CaCo2-ras cells, but not parental CaCo2, express high levels of the human NT/N gene and, moreover, that this increase in gene expression is regulated at the level of transcription. Transfection experiments using NT/N-CAT mutation constructs identify the proximal 200 bp of NT/N flanking sequence as sufficient for maximal Ras-mediated NT/N reporter gene induction. Furthermore, a proximal AP-1/CRE motif is crucial for this Ras-mediated NT/N activation. Wild-type Ha-ras induces NT/N gene expression, albeit at lower levels than activated Ras; a dominant-negative Raf blocks this NT/N induction, suggesting that Raf lies down-stream of Ras in this pathway. In addition, postconfluent cultures of CaCo2 cells, which are differentiated to a small bowel phenotype, express the NT/N gene by 6 d after reaching confluency; this increase of NT/N expression is associated with concomitant increases of cellular p21ras protein. We conclude that Ras (both wild-type and activated) enhances expression of the NT/N gene in the gut-derived CaCo2 cell line, suggesting an important role for the Ras signaling pathway in NT/N gene transcription. Our results underscore the possibility that tissue-specific genes (such as NT/N) expressed in distinct subpopulations of the gut may be subject to Ras regulation. Finally, we speculate that the NT/N gene and the CaCo2 and CaCo2-ras cell systems will provide unique models to further define the cellular mechanisms leading to mammalian intestinal differentiation.

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