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J. Biol. Chem., Vol. 275, Issue 41, 32122-32128, October 13, 2000
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From the Departments of Although ectopic expression of the
cholecystokinin B/gastrin receptor (CCK-BR) is widely reported in human
colorectal cancers, its role in mediating the proliferative effects of
gastrin1-17 (G-17) on these cancers is unknown. Here we report the
isolation of a novel splice variant of CCK-BR that exhibits
constitutive (ligand-independent) activation of pathways regulating
intracellular free Ca2+
([Ca2+]i) and cell growth. The splice variant
(designated CCK-BRi4sv for intron 4-containing splice variant) is
expressed in colorectal cancers but not in normal colonic mucosa
adjacent to the cancer. Balb3T3 cells expressing CCK-BRi4sv exhibited
spontaneous, ligand-independent, oscillatory increases in
[Ca2+]i, whereas cells expressing wild-type
CCK-BR did not. Primary cultures of cells isolated from resected
colorectal cancers also exhibited a similar pattern of spontaneous
[Ca2+]i oscillations. For both Balb3T3 and
primary tumor cells, application of G-17 (10 and 200 nM,
respectively) caused an increase in [Ca2+]i.
Selective CCK-BR antagonists blocked the G-17-stimulated Ca2+ responses but not the spontaneous
[Ca2+]i oscillations. Cells expressing CCK-BRi4sv
exhibited an increased growth rate (~2.5-fold), in the absence of
G-17, compared with cells expressing wild-type CCK-BR. The selective pattern of expression, constitutive activity, and trophic action associated with CCK-BRi4sv suggest that this variant may regulate colorectal cancer cell proliferation though a gastrin-independent mechanism.
The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EMBL Data Bank with accession number(s) AF239668.
Human Colorectal Cancers Express a Constitutively Active
Cholecystokinin-B/Gastrin Receptor That Stimulates Cell Growth*
§¶,,
,,, and
Surgery,
§ Physiology and Biophysics, and Internal
Medicine, the University of Texas Medical Branch,
Galveston, Texas 77555
*
This work was supported by National Institutes of Health
Grant R01DK48345 (to C. M. T.) and an American Cancer Society
institutional grant (to M. R. H.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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