Gastrin-induced proliferation involves MEK partner 1 (MP1)

Steigedal, Tonje S.; Prestvik, Wenche S.; Selvik, Linn-Karina M.; Fjeldbo, Christina S.; Bruland, Torunn; Lægreid, Astrid; Thommesen, Liv

doi:10.1007/s11626-013-9588-2

Cited by 18 publications

(11 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We have recently shown that the gastrin induced MAPK scaffold protein MEK partner 1 (MP1) is important for gastrin induced phosphorylation of ERK1 and ERK2 in the human gastric adenocarcinoma cell line AGS-G R [53]. Qualitative and quantitative differences in ERK activity can also be regulated at the receptor level [49].…”

Section: Resultsmentioning

confidence: 99%

The duration of gastrin treatment affects global gene expression and molecular responses involved in ER stress and anti-apoptosis

et al. 2013

Self Cite

View full text Add to dashboard Cite

BackgroundHow cells decipher the duration of an external signal into different transcriptional outcomes is poorly understood. The hormone gastrin can promote a variety of cellular responses including proliferation, differentiation, migration and anti-apoptosis. While gastrin in normal concentrations has important physiological functions in the gastrointestine, prolonged high levels of gastrin (hypergastrinemia) is related to pathophysiological processes.ResultsWe have used genome-wide microarray time series analysis and molecular studies to identify genes that are affected by the duration of gastrin treatment in adenocarcinoma cells. Among 403 genes differentially regulated in transiently (gastrin removed after 1 h) versus sustained (gastrin present for 14 h) treated cells, 259 genes upregulated by sustained gastrin treatment compared to untreated controls were expressed at lower levels in the transient mode. The difference was subtle for early genes like Junb and c-Fos, but substantial for delayed and late genes. Inhibition of protein synthesis by cycloheximide was used to distinguish between primary and secondary gastrin regulated genes. The majority of gastrin upregulated genes lower expressed in transiently treated cells were primary genes induced independently of de novo protein synthesis. This indicates that the duration effect of gastrin treatment is mainly mediated via post-translational signalling events, while a smaller fraction of the differentially expressed genes are regulated downstream of primary transcriptional events. Indeed, sustained gastrin treatment specifically induced prolonged ERK1/2 activation and elevated levels of the AP-1 subunit protein JUNB. Enrichment analyses of the differentially expressed genes suggested that endoplasmic reticulum (ER) stress and survival is affected by the duration of gastrin treatment. Sustained treatment exerted an anti-apoptotic effect on serum starvation-induced apoptosis via a PKC-dependent mechanism. In accordance with this, only sustained treatment induced anti-apoptotic genes like Clu, Selm and Mcl1, while the pro-apoptotic gene Casp2 was more highly expressed in transiently treated cells. Knockdown studies showed that JUNB is involved in sustained gastrin induced expression of the UPR/ER stress related genes Atf4, Herpud1 and Chac1.ConclusionThe duration of gastrin treatment affects both intracellular signalling mechanisms and gene expression, and ERK1/2 and AP-1 seem to play a role in converting different durations of gastrin treatment into distinct cellular responses.

show abstract

Section: Resultsmentioning

confidence: 99%

The duration of gastrin treatment affects global gene expression and molecular responses involved in ER stress and anti-apoptosis

et al. 2013

Self Cite

View full text Add to dashboard Cite

show abstract

“…Gastrin and/or its receptor have been identified in a number of tissues and tumor types (e.g., Barrett's esophagus, gastric adenocarcinoma, pancreatic adenocarcinoma, and colonic adenocarcinoma) in which it may promote growth and induce oncogenic transformation [31]. Amidated gasrin-34 and gasrin-17, as well as the CCK2R, are detectable in 80% of human gastric adenocarcinomas [32 & ].…”

Section: Key Pointsmentioning

confidence: 99%

Gastric secretion

Schubert

2014

Current Opinion in Gastroenterology

View full text Add to dashboard Cite

show abstract

“…We and others have shown that gastrin regulates several important cellular processes in the gastric epithelium and in adenocarcinoma cells including proliferation [1], anti-apoptosis [2], [3], [4], migration [5] and invasion [6]. Functional genomics approaches have identified a range of new gastrin target genes [3], [4], [7], [8], [9].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2014

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Gastrin-induced proliferation involves MEK partner 1 (MP1)

Cited by 18 publications

References 41 publications

The duration of gastrin treatment affects global gene expression and molecular responses involved in ER stress and anti-apoptosis

The duration of gastrin treatment affects global gene expression and molecular responses involved in ER stress and anti-apoptosis

Gastric secretion

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

Contact Info

Product

Resources

About