Inducible cAMP early repressor suppresses gastrin-mediated activation of cyclin D1 and c-<i>fos</i>gene expression

Steigedal, Tonje S.; Bruland, Torunn; Misund, Kristine; Thommesen, Liv; Lægreid, Astrid

doi:10.1152/ajpgi.00287.2006

Cited by 14 publications

(13 citation statements)

References 54 publications

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“…The evidence that ICER acts as a tumor suppressor gene in leukemia cell line HL60, as reported previously for other solid tumors, [28][29][30] first comes from the decreased clonogenicity ability of HL60 þ ICER cells in vitro. We used immunodeficent mice to confirm these data and reveal that HL60 þ ICER-injected mice have a mild leukemia phenotype for the reduced dissemination of tumor in extramedullary sites.…”

Section: Discussionsupporting

confidence: 65%

ICER expression inhibits leukemia phenotype and controls tumor progression

et al. 2008

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The inducible cyclic AMP (cAMP) early repressor (ICER) and cAMP response element-binding protein (CREB) are transcriptional regulators of the cAMP-mediated signaling pathway. CREB has been demonstrated to be upregulated in the majority of childhood leukemias contributing to disease progression, whereas ICER, its endogenous repressor, was found to be downregulated. Our research focus has been the function of restored ICER expression. ICER exogenously expressed in cell lines decreases CREB protein level and induces a lowered clonogenic potential in vitro. It decreases the ability of HL60 to invade the extramedullary sites and to promote bone marrow angiogenesis in nonobese diabetic-severe combined immunodeficient mice, demonstrating its potential effects on tumor progression. ICER represses the majority of 96 target genes upregulated by CREB. It binds CRE promoters and controls gene expression restoring the normal regulation of major cellular pathways. ICER is subjected to degradation through a constitutively active form of the extracellular signal-regulated protein kinase, which drives it to the proteasome. We propose that ICER is downregulated in HL60 to preserve CREB overexpression, which disrupts normal myelopoiesis and promotes blast proliferation. These findings define the function of ICER as a tumor suppressor in leukemia. Unbalanced CREB/ICER expression needs to be considered a pathogenetic feature in leukemogenesis. The molecular characterization of this pathway could be useful for novel therapeutic strategies.

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Section: Discussionsupporting

confidence: 65%

ICER expression inhibits leukemia phenotype and controls tumor progression

et al. 2008

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“…We and others have previously shown that c-fos is activated by gastrin [23], [31], [32], and we thus wanted to explore a possible role of SIK1 in gastrin-induced c-fos activation. AGS-G R cells with ectopically expressed SIK1 showed a two-fold increase in gastrin-induced c- fos- luc transcription compared to control cells (Figure 3A).…”

Section: Resultsmentioning

confidence: 99%

“…Cells (5.0×10 5 /well) in six-well plates were harvested in 0.5 ml SDS-sample buffer and subjected to western blot analysis as described previously [23]. Binding of secondary antibodies was visualized by the Super Signal West Femto Maximum Sensitivity Substrate (Pierce, Rockford, IL) and Kodak Image Station 2000R (Kodak, Pittsburgh, PA).…”

Section: Methodsmentioning

confidence: 99%

Salt-Inducible Kinase 1 (SIK1) Is Induced by Gastrin and Inhibits Migration of Gastric Adenocarcinoma Cells

et al. 2014

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Salt-inducible kinase 1 (SIK1/Snf1lk) belongs to the AMP-activated protein kinase (AMPK) family of kinases, all of which play major roles in regulating metabolism and cell growth. Recent studies have shown that reduced levels of SIK1 are associated with poor outcome in cancers, and that this involves an invasive cellular phenotype with increased metastatic potential. However, the molecular mechanism(s) regulated by SIK1 in cancer cells is not well explored. The peptide hormone gastrin regulates cellular processes involved in oncogenesis, including proliferation, apoptosis, migration and invasion. The aim of this study was to examine the role of SIK1 in gastrin responsive adenocarcinoma cell lines AR42J, AGS-GR and MKN45. We show that gastrin, known to signal through the Gq/G11-coupled CCK2 receptor, induces SIK1 expression in adenocarcinoma cells, and that transcriptional activation of SIK1 is negatively regulated by the Inducible cAMP early repressor (ICER). We demonstrate that gastrin-mediated signalling induces phosphorylation of Liver Kinase 1B (LKB1) Ser-428 and SIK1 Thr-182. Ectopic expression of SIK1 increases gastrin-induced phosphorylation of histone deacetylase 4 (HDAC4) and enhances gastrin-induced transcription of c-fos and CRE-, SRE-, AP1- and NF-κB-driven luciferase reporter plasmids. We also show that gastrin induces phosphorylation and nuclear export of HDACs. Next we find that siRNA mediated knockdown of SIK1 increases migration of the gastric adenocarcinoma cell line AGS-GR. Evidence provided here demonstrates that SIK1 is regulated by gastrin and influences gastrin elicited signalling in gastric adenocarcinoma cells. The results from the present study are relevant for the understanding of molecular mechanisms involved in gastric adenocarcinomas.

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“…We (Ref. 53 and unpublished data), as well as others (55), have shown that gastrin induces expression of genes encoding members of the AP-1 complex, like c-fos and junB. To investigate AP-1 as a possible mediator of gastrin-induced expression of clusterin, AR42J cells were transfected with reporter plasmids containing the luciferase gene driven by the rat clusterin promoter with or without the AP-1 site.…”

Section: Gastrin Increases Expression Of Clusterin In Adenocarcinoma mentioning

confidence: 99%

Gastrin upregulates the prosurvival factor secretory clusterin in adenocarcinoma cells and in oxyntic mucosa of hypergastrinemic rats

Fjeldbo

Bakke

Erlandsen

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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Fjeldbo CS, Bakke I, Erlandsen SE, Holmseth J, Laegreid A, Sandvik AK, Thommesen L, Bruland T. Gastrin upregulates the prosurvival factor secretory clusterin in adenocarcinoma cells and in oxyntic mucosa of hypergastrinemic rats. Am J Physiol Gastrointest Liver Physiol 302: G21-G33, 2012. First published October 13, 2011 doi:10.1152/ajpgi.00197.2011We show that the gastric hormone gastrin induces the expression of the prosurvival secretory clusterin (sCLU) in rat adenocarcinoma cells. Clusterin mRNA was still upregulated in the presence of the protein synthesis inhibitor cycloheximide, although at a lower level. This indicates that gastrin induces clusterin transcription independently of de novo protein synthesis but requires de novo protein synthesis of signal transduction pathway components to achieve maximal expression level. Luciferase reporter assay indicates that the AP-1 transcription factor complex is involved in gastrin-mediated activation of the clusterin promoter. Gastrininduced clusterin expression and subsequent secretion is dependent on sustained treatment, because removal of gastrin after 1-2 h abolished the response. Neutralization of secreted clusterin by a specific antibody abolished the antiapoptotic effect of gastrin on serum starvationinduced apoptosis, suggesting that extracellular clusterin is involved in gastrin-mediated inhibition of apoptosis. The clusterin response to gastrin was validated in vivo in hypergastrinemic rats, showing increased clusterin expression in the oxyntic mucosa, as well as higher levels of clusterin in plasma. In normal rat oxyntic mucosa, clusterin protein was strongly expressed in chromogranin A-immunoreactive neuroendocrine cells, of which the main cell type was the histidine decarboxylase-immunoreactive enterochromaffin-like (ECL) cell. The association of clusterin with neuroendocrine differentiation was further confirmed in human gastric ECL carcinoids. Interestingly, in hypergastrinemic rats, clusterin-immunoreactive cells formed distinct groups of diverse cells at the base of many glands. Our results suggest that clusterin may contribute to gastrin's growth-promoting effect on the oxyntic mucosa. apoptosis; AR42J cells; reverse transfection; neuroendocrine cells; carcinoids THE PEPTIDE HORMONE GASTRIN is important in maintenance of architecture and function of the acid-secreting (oxyntic) mucosa of the stomach. It is a well-recognized regulator of gastric acid secretion and exerts a general growth-promoting effect on the gastric mucosa. Prolonged elevated plasma gastrin levels (hypergastrinemia), particularly in conjunction with inflammation, may play a role in gastrointestinal carcinogenesis (12,13,60). The gastric mucosa is under constant renewal, and both proliferation and apoptosis are important components for maintaining homeostasis (21, 46). Although most research has concentrated on gastrin's proliferation-inducing effect (30), recent evidence suggests that it is also a potent inhibitor of cellular apoptosis (33,45,47,54,56). Thus both stimulation o...

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Inducible cAMP early repressor suppresses gastrin-mediated activation of cyclin D1 and c-fosgene expression

Cited by 14 publications

References 54 publications

ICER expression inhibits leukemia phenotype and controls tumor progression

ICER expression inhibits leukemia phenotype and controls tumor progression

Salt-Inducible Kinase 1 (SIK1) Is Induced by Gastrin and Inhibits Migration of Gastric Adenocarcinoma Cells

Gastrin upregulates the prosurvival factor secretory clusterin in adenocarcinoma cells and in oxyntic mucosa of hypergastrinemic rats

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