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Am J Physiol Gastrointest Liver Physiol (October 16, 2002). doi:10.1152/ajpgi.00351.2002
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Articles in PresS, published online ahead of print October 16, 2002
Am J Physiol Gastrointest Liver Physiol, 10.1152/ajpgi.00351.2002
Submitted on August 20, 2002
Accepted on October 7, 2002

The prohormone, progastrin1-80, stimulates growth of intestinal epithelial cells in vitro via high affinity binding sites

Pomila Singh1*, Xian B Lu2, Stephanie L Cobb1, B. T Miller1, Nayda Tarasova3, Andrea Varro4, and Azarmidokht Owlia1

1 Department of Anatomy and Neurosciences, University of Texas Medical Branch, Galveston, TX, USA
2 Elim Biopharmaceuticals, Inc., South San Francisco, CA, USA
3 National Cancer Institute, Fredericksburg, MD, USA
4 Department of Physiology, University of Liverpool, Liverpool, United Kingdom

* To whom correspondence should be addressed. E-mail: posingh{at}utmb.edu.

Proliferation and carcinogenesis of the large intestinal epithelial cells is significantly increased in transgenic mice, over-expressing the precursor progastrin (PG) peptide. It is not known if the in vivo growth effects of PG on intestinal epithelial cells (IEC) are mediated directly or indirectly. Full-length recombinant human PG (rhPG1-80) was generated to examine possible direct effects of PG on IEC cells. Surprisingly rhPG (01.-1.0 nM) was more effective than the completely processed G17 peptide as a growth factor. Even though IEC cells did not express CCK1 and CCK2-receptors (R), fluorescently labeled G17 and gly-extended G17 (G-Gly) were specifically bound to the cells, suggesting the presence binding proteins other than CCK1 and CCK2-R on IEC cells. High affinity (Kd = 0.5-1.0 nM) binding sites for 125I-rhPG were discovered on IEC cells that demonstrated relative binding affinity for gastrin-like peptides in the order PG >= C-terminally extended G17 by 8 amino acids (G17-CT)>=G-Gly>G17>*CCK-8 (*=p<0.05). In conclusion, our studies demonstrate for the first time direct growth effects of the full-length precursor peptide on IEC cells, in vitro, that are apparently mediated by the high affinity PG binding sites that were discovered on these cells.




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