Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01350 (gastrin)
 9,683 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Suppression of the gastrin gene in human colon cancer cells by stably expressing antisense (AS) gastrin RNA results in significant growth suppression of AS cells. To understand mechanisms mediating the growth effects of autocrine gastrins, differential expression of transcripts by AS and control (C) clones of a representative cell line (HCT-116) was analyzed to identify target genes of autocrine gastrins. Six differentially expressed transcripts were confirmed and sequenced. Of these, the RNA and protein levels of cytochrome c oxidase (COX) Vb were significantly higher in C versus AS cells. The expression of COX Vb by colon cancer cells was proportional to the expression of gastrin. Higher levels of COX Vb coprecipitated with cytochrome c in the mitochondria of C versus AS cells. Treatment of mitochondria with digitonin resulted in a 2-fold higher release of cytochrome c from AS versus C mitochondria. As a corollary, the cytosolic levels of cytochrome c were significantly higher in AS versus C cells, which correlated with approximately 2- and approximately 3-fold higher activation of caspase-9 and -3, respectively, in AS versus C cells in response to camptothecin. Thus, autocrine gastrins may support growth/survival of cells by up-regulating COX Vb, which may decrease the sensitivity of the cancer cells to apoptotic stimuli by increasing retention of cytochrome c in mitochondria.
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PMID:Autocrine gastrins in colon cancer cells Up-regulate cytochrome c oxidase Vb and down-regulate efflux of cytochrome c and activation of caspase-3. 1091 81

The role of the gastrin peptide hormones (G17, G34) and their precursors (progastrins, PG; gly-extended gastrin, G-gly), in gastrointestinal (GI) cancers has been extensively reviewed in recent years [W. Rengifo-Cam, P. Singh, Role of progastrins and gastrins and their receptors in GI and pancreatic cancers: targets for treatment, Curr. Pharm. Des. 10 (19) (2004) 2345-2358; M. Dufresne, C. Seva, D. Fourmy, Cholecystokinin and gastrin receptors, Physiol. Rev. 86 (3) (2006) 805-847; A. Ferrand, T.C. Wang, Gastrin and cancer: a review, Cancer Lett. 238 (1) (2006) 15-29]. A possible important role of progastrin peptides in colon carcinogenesis has become evident from experiments with transgenic mouse models [W. Rengifo-Cam, P. Singh, (2004); A. Ferrand, T.C. Wang, (2006)]. It is now known that growth stimulatory and co-carcinogenic effects of gastrin/PG peptides are mediated by both proliferative and anti-apoptotic effects of the peptides on target cells [H. Wu, G.N. Rao, B. Dai, P. Singh, Autocrine gastrins in colon cancer cells Up-regulate cytochrome c oxidase Vb and down-regulate efflux of cytochrome c and activation of caspase-3, J. Biol. Chem. 275 (42) (2000) 32491-32498; H. Wu, A. Owlia, P. Singh, Precursor peptide progastrin(1-80) reduces apoptosis of intestinal epithelial cells and upregulates cytochrome c oxidase Vb levels and synthesis of ATP, Am. J. Physiol. Gastrointest. Liver Physiol. 285 (6) (2003) G1097-G1110]. Several receptor subtypes have been described that mediate growth effects of gastrin peptides [W. Rengifo-Cam, P. Singh (2004); M. Dufresne, C. Seva, D. Fourmy, (2006)]. Recently, we identified Annexin II as a high affinity binding protein for gastrin/PG peptides [P. Singh, H. Wu, C. Clark, A. Owlia, Annexin II binds progastrin and gastrin-like peptides, and mediates growth factor effects of autocrine and exogenous gastrins on colon cancer and intestinal epithelial cells, Oncogene (2006), doi:10.1038/sj.onc.1209798]. Importantly, the expression of Annexin II was required for mediating growth stimulatory effects of gastrin and PG peptides on intestinal epithelial and colon cancer cells [P. Singh, H. Wu, C. Clark, A. Owlia, Annexin II binds progastrin and gastrin-like peptides, and mediates growth factor effects of autocrine and exogenous gastrins on colon cancer and intestinal epithelial cells, Oncogene (2006), doi:10.1038/sj.onc.1209798], suggesting that Annexin-II may represent the elusive novel receptor for gastrin/PG peptides. The importance of this finding in relation to the structure and function of Annexin-II, especially in GI cancers, is described below. Since this surprising finding represents a new front in our understanding of the mechanisms involved in mediating growth effects of gastrin/PG peptides in GI cancers, our current understanding of the role of Annexin-II in proliferation and metastasis of cancer cells is additionally reviewed.
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PMID:Role of Annexin-II in GI cancers: interaction with gastrins/progastrins. 1718 24