COOH-terminal 26-amino acid residues of progastrin are sufficient for stimulation of mitosis in murine colonic epithelium in vivo

Ottewell, Penelope D.; Varró, Andrea; Dockray, Graham J.; Kirton, Chris M.; Watson, Alastair; Wang, T. C.; Dimaline, R.; Pritchard, D. Mark

doi:10.1152/ajpgi.00268.2004

Cited by 36 publications

(31 citation statements)

References 43 publications

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“…One possibility is that CCK2R is a direct downstream target of progastrin, and indeed receptor mRNA expression was upregulated in hGAS /+ colon. On the other hand, our previous studies with hGAS /+ /GAS knockout mice have shown that progastrin is able to stimulate colonic proliferation in the absence of amidated gastrin (12), which is contradictory to another report (13). Formally, another possibility is that CCK2R deficiency results in a dominant inhibitory cancer phenotype independent of progastrin effects.…”

Section: Figurecontrasting

confidence: 64%

“…Furthermore, progastrin overexpression or exogenous administration could maintain colonic epithelial mitosis after DNA damage by γ irradiation or chemical carcinogens (11). These effects of progastrin were not dependent on other forms of gastrin, since progastrin-expressing hGAS mice showed a similar phenotype when crossed with a gastrin knockout background (12). Nevertheless, there has been a report on increased azoxymethane-induced (AOM-induced) carcinogenesis in GAS knockout mice (13), in contrast to our findings of decreased colonic proliferation, polyposis, and prolonged survival when crossed to Apc/Min mice (14,15).…”

Section: Introductionmentioning

confidence: 98%

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Inactivating cholecystokinin-2 receptor inhibits progastrin-dependent colonic crypt fission, proliferation, and colorectal cancer in mice

Jin

Ramanathan²,

Quante³

et al. 2009

J. Clin. Invest.

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Hyperproliferation of the colonic epithelium, leading to expansion of colonic crypt progenitors, is a recognized risk factor for colorectal cancer. Overexpression of progastrin, a nonamidated and incompletely processed product of the gastrin gene, has been shown to induce colonic hyperproliferation and promote colorectal cancer in mice, but the mechanism of pathogenesis has not been defined. Cholecystokinin-2 receptor (CCK2R) is the primary receptor for cholecystokinin (CCK) and amidated gastrin. Here, we show that Cck2r was expressed in murine colonic crypts and upregulated in the transgenic mice that overexpress human progastrin. Murine deletion of Cck2r abrogated progastrin-dependent increases in colonic proliferation, mucosal thickness, and β-catenin and CD44 expression in the colon tumor. In addition, either deletion or antagonism of Cck2r resulted in the inhibition of progastrin-dependent increases in progenitors expressing doublecortin and CaM kinase-like-1 (DCAMKL1), stem cells expressing leucine rich repeat-containing G protein-coupled receptor 5 (LgR5), and colonic crypt fission. Furthermore, in the azoxymethane mouse model of colorectal carcinogenesis, Cck2r deletion in human progastrin-overexpressing mice resulted in markedly decreased aberrant crypt foci formation and substantially reduced tumor size and multiplicity. Taken together, these observations indicate that progastrin induces proliferative effects, primarily in colonic progenitor cells, through a CCK2R-dependent pathway. Moreover, our data suggest that CCK2R may be a potential target in the treatment or prevention of colorectal cancer.

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Section: Figurecontrasting

confidence: 64%

Section: Introductionmentioning

confidence: 98%

Inactivating cholecystokinin-2 receptor inhibits progastrin-dependent colonic crypt fission, proliferation, and colorectal cancer in mice

Jin

Ramanathan²,

Quante³

et al. 2009

J. Clin. Invest.

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“…The larger precursor 80 amino acid progastrin peptide also stimulates proliferation of colon cancer cell lines , inhibits pancreatic cancer apoptosis (Rengifo-Cam et al 2007), and transgenic mice over-expressing progastrin exhibit colonic hyperproliferation, increased mitosis after irradiation and adenomata and carcinomas after exposure to the chemical carcinogen azoxymethane (Cobb et al 2004, Ottewell et al 2005.…”

Section: Introductionmentioning

confidence: 99%

Glycine-extended gastrin inhibits apoptosis in Barrett's oesophageal and oesophageal adenocarcinoma cells through JAK2/STAT3 activation

Beales

Ogunwobi²

2009

Journal of Molecular Endocrinology

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Barrett's oesophagus (BO) and oesophageal adenocarcinoma (OAC) are regarded as complications of gastrooesophageal reflux disease, although all the factors that contribute to the development of these lesions are unknown. Acid suppressive drugs are widely used for symptomatic therapy of reflux disease but may induce hypersecretion of gastrin peptides. Amidated gastrin (G-17) has been shown to be a growth factor for OAC cells. We have examined the effects of glycine-extended gastrin (G-Gly), an alternative product of progastrin processing on apoptosis in the QhERT Barrett's oesophageal cell line and OE33 and BIC-1 OAC cells. G-Gly inhibited serum-starvation and camptothecininduced apoptosis in all three cell lines, G-17 was only effective in OE33 cells. By contrast to the effects of G-17, the antiapoptotic effect of G-Gly was independent of both the CCK 2 receptor and cyclo-oxygenase-2 activity. G-Gly stimulated JAK2 phosphorylation and kinase activity and JAK2-dependent STAT3 phosphorylation and transcriptional activity. G-Gly also increased mRNA and protein levels of the anti-apoptotic proteins survivin and BCL2L1 but did not affect the levels of BAD, BAX or BCL-2. Novel small molecule inhibitors of JAK2 and STAT3 as well as STAT3 siRNA blocked the anti-apoptotic effects of G-Gly and inhibited the induction of survivin and BCL2L1 in OE33 cells. We conclude that G-Gly inhibits apoptosis in BO and OAC via mechanisms distinct from those activated by G-17 and involving JAK2 and STAT3 activation. Release of gastrin peptides in response to acid suppressive therapy may adversely influence the dynamics of the epithelium in BO.

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“…PG, GG and G17 exert proliferative effects on normal and cancerous gastrointestinal (GI) cells in vitro and in vivo (Wang et al, 1996;Hollande et al, 1997;Koh et al, 1999;Baldwin et al, 2001;Brown et al, 2003;Singh et al, 2003;Ottewell et al, 2005). PG and GG exert cocarcinogenic effects on colon carcinogenesis in response to azoxymethane (Singh et al, 2000a, b;Aly et al, 2001;Cobb et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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

Singh

Clark³

et al. 2006

Oncogene

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We and others have reported the presence of novel progastrin (PG)/gastrin receptors on normal and cancerous intestinal cells. We had earlier reported the presence of 33-36 kDa gastrin-binding proteins on cellular membranes of colon cancer cells. The goal of the current study was to identify the protein(s) in the 33-36 kDa band, and analyse its functional significance. A carbodiimide crosslinker was used for crosslinking radio-labeled gastrins to membrane proteins from gastrin/PG responsive cell lines. Native membrane proteins, crosslinked to the ligand, were solubulized and enriched by >1000-fold, and analysed by surface-enhanced laser desorption/ ionization-time of flight-mass spectrometry. The peptide masses were researched against the NCBInr database using the ProFound search engine. Annexin II (ANX II) was identified, and confirmed by matrix-assisted laser desorption/ionization-time of flight-mass spectrometry. As HCT-116 cells express autocrine PG, the in situ association of PG with ANX II was demonstrated in pulldown assays. Direct binding of PG with ANX II was confirmed in an in vitro binding assay. In order to confirm a functional importance of these observations, sense and anti-sense (AS) ANX II RNA-expressing clones of intestinal epithelial (IEC-18) and human colon cancer (HCT-116) cell lines were generated. AS clones demonstrated a significant loss in the growth response to exogenous (IEC-18) and autocrine (HCT-116) PG. We have thus discovered that membrane-associated ANX II binds PG/gastrins, and partially mediates growth factor effects of the peptides.

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COOH-terminal 26-amino acid residues of progastrin are sufficient for stimulation of mitosis in murine colonic epithelium in vivo

Cited by 36 publications

References 43 publications

Inactivating cholecystokinin-2 receptor inhibits progastrin-dependent colonic crypt fission, proliferation, and colorectal cancer in mice

Inactivating cholecystokinin-2 receptor inhibits progastrin-dependent colonic crypt fission, proliferation, and colorectal cancer in mice

Glycine-extended gastrin inhibits apoptosis in Barrett's oesophageal and oesophageal adenocarcinoma cells through JAK2/STAT3 activation

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

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