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Gastrointestinal Surgical Pathobiology Research Group, Yale University School of Medicine and the West Haven Veterans Affairs Medical Center, New Haven, Connecticut 06520-8062
We have previously demonstrated that in
Mastomys species proliferation of gastric
enterochromaffin-like (ECL) cells is predominantly regulated by gastrin
and by transforming growth factor-
(TGF-
) in the naive and
neoplastic state, respectively. In this study we examined whether these
intracellular mitogenic responses are mediated by polyamines and
ornithine decarboxylase (ODC), the rate-limiting enzyme for polyamine
biosynthesis. An ECL cell preparation of high purity was used to
measure the effect of the polyamine derivatives putrescine, spermidine,
and spermine on DNA synthesis by bromodeoxyuridine uptake. Both
putrescine and spermidine augmented gastrin-stimulated, but not basal,
DNA synthesis in naive cells. This proliferative response correlated
with an increase in ODC activity that was partially inhibited (20%) by
difluoromethylornithine (DFMO), an inhibitor of ODC
(IC50, 30 pM). In
contrast, all polyamines increased both basal and TGF-
-stimulated
DNA synthesis as well as ODC activity in tumor ECL cells. DFMO
completely inhibited the proliferative response of TGF-
(IC50, 3 pM). Thus polyamine biosynthesis is involved in proliferation of ECL cells and in particular the mitogenesis of tumor cells, suggesting a role for this
pathway in the regulation of ECL cell transformation.
gastrin; ornithine decarboxylase; transforming growth factor-
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M. Kidd, T. Hinoue, G. Eick, K. D. Lye, S. M. Mane, Y. Wen, and I. M. Modlin Global expression analysis of ECL cells in Mastomys natalensis gastric mucosa identifies alterations in the AP-1 pathway induced by gastrin-mediated transformation Physiol Genomics, December 15, 2004; 20(1): 131 - 142. [Abstract] [Full Text] [PDF] |
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