Transcription profiling of Mus musculus gastric Lkb1 polyps vs unaffected gastric Lkb1 mucosa
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Lina Udd-Granat
PROVIDER: E-MEXP-2444 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
Project description:Inherited mutation in LKB1 results in the Peutz-Jeghers syndrome (PJS), characterized by intestinal hamartomas and a modestly increased frequency of gastrointestinal and breast cancer1. Somatic inactivation of LKB1 occurs in human lung adenocarcinoma2-4, but its tumor suppressor role in this tissue is unknown. Here we show that somatic Lkb1 deficiency strongly cooperates with somatic K-rasG12D activating mutation to accelerate the development of mouse lung tumorigenesis. Lkb1 deficiency in the setting of K-rasG12D mutation (K-ras Lkb1L/L) was associated with decreased tumor latency and increased tumor aggressiveness including metastasis. Furthermore, tumors from K-ras Lkb1L/L mice demonstrated histologies--squamous, adenosquamous and large cell--not seen with K-rasG12D mutation, Ink4a/Arf inactivation, or p53 inactivation alone or in combination. Experiments in vitro suggest that LKB1 suppresses lung tumorigenesis and progression through both p16INK4a-ARF-p53 dependent and independent mechanisms. These data indicate that LKB1 regulates lung tumor progression and differentiation. Keywords: cancer research To analyze the role of LKB1 in lung cancer progression and differentiation, we have dissected the lung tumors from mice with/without lkb1 loss and performed the microarray analyses to compare their gene expression pattern. In addition, we have also performed microarray analysis in both A549 and H2126 cell lines after reconsistitution of either wt-lkb1 or the kinase dead form of lkb1 (lkb1-KD) to confirm what we observed from in vivo studies.
2007-08-28 | E-GEOD-6135 | biostudies-arrayexpress
Project description:LKB1 encodes a Ser/Thr kinase and acts as an evolutionarily conserved sensor of cellular energy status in eukaryotic cells. LKB1 functions as the major upstream kinase to phosphorylate AMPK and 12 other AMPK-related kinases, which is required for their activation in many cellular contexts. Once activated, AMPK and AMPK-related kinases phosphorylate a diverse array of downstream effectors to switch on ATP-generating catabolic processes and switch off ATP-consuming anabolic processes, thus restoring energy balance during periods of energetic stress. To study the role and mechanisms of Lkb1 in the regulation of hematopoietic stem cell (HSC) biology, we performed transcriptome analysis of sorted LSK (Lin-, Sca-1+, c-Kit+) cells from Lkb1 WT and KO bone marrows at 1 day post-completing tamoxifen injection (DPI). To identify more proximal molecular effects, we chose 1 DPI due to the modest phenotypes in Lkb1 KO mice, yet documentation of efficient Lkb1 deletion in LSK cells at this very early time point. We treated Lkb1 L/L rosa26CreERT2 and Lkb1 L/L mice (C57BL/Ka-CD45.2:Thy-1.1 background) with Tamoxifen for 5 days to somatically delete Lkb1 in adult mice, and generated Lkb1 WT and KO mice. At 1 DPI, we prepared single-cell suspensions from bone marrow (from femoral and tibial bones), and stained and sorted LSK populations using FACSAria (Becton Dickinson, Mountain View, CA). The RNA was extracted from sorted LSK cells, amplified and subjected to gene profiling. The samples include 3 Lkb1 WT (Lkb1 WT 5-7) and 4 Lkb1 KO (Lkb1 KO 4-7) replicates.
2010-12-01 | E-GEOD-24765 | biostudies-arrayexpress
Project description:LKB1 is a tumor suppressor lost in approximately 30% of lung adenocarcinomas. It is a serine-threonine kinase involved in regulating metabolism, proliferation, and cell polarity. We have characterized its association with mRNA expression profiles in resected tumors and in cell lines, but little is known about the direct effects of LKB1 on the regulation of these genes. This study investigates the effects of LKB1 activity on mRNA expression in two LKB1-mutant lung adenocarcinoma cell lines, H2122 and A549. Wild-type LKB1 has been stably expressed in these cell lines using a pBABE retrovirus as well as an empty pBABE control and a kinase-dead mutant of LKB1 (K78I) control (Addgene). Samples submitted are two cell lines, three experimental conditions, and three replicates, for a total of 17 samples (one sample was excluded for poor RNA quality). Gene expression of these samples are analyzed to determine transcriptional regulatory effects of LKB1 expression. Results of this analysis are compared to our analysis of resected human tumors to determine gene patterns that are differentially expressed between LKB1-deficient and LKB1-wild-type tumors whose expression is also affected by restoration of LKB1 in vitro. RMA gene expression was taken from two cell lines stably expressing LKB1 or controls of K78I mutant LKB1 or empty pBABE vector. Log2 average expression differences are calculated and compared to results from analysis of gene expression associated with LKB1 loss in resected human tumors.
2013-10-01 | E-GEOD-51266 | biostudies-arrayexpress
Project description:Perturbed intestinal epithelial homeostasis demonstrated as decreased Lgr5+ intestinal stem cells (Lgr5 ISCs) and increased secretory lineages were observed in our study where Lkb1 was specfically deleted in Lgr5 ISCs using Lgr5-EGFP-creERT2 (Tamoxifen) deletor. To gain mechanistic insight how Lkb1 maintains intestinal epithelial stem cell homeostasis, Lkb1 deficient ISCs (Lgr5-high cells) and progenitors (Lgr5-low cells) are isolated by flow cytometry and profiled by RNA sequencing to compare with controls (Lkb1 wild type ISCs and progenitors).
2020-02-29 | E-MTAB-6501 | biostudies-arrayexpress
Project description:Excessive glucose production in the liver is a key factor in the hyperglycemia observed in diabetes mellitus type 2. It is generally agreed to result from an increase in hepatic gluconeogenesis. Considerable attention has been devoted to the transcriptional regulation of key gluconeogenic enzymes, but much less is known about the regulation of amino-acid catabolism, which generates gluconeogenic substrates. Here, we highlight a novel role of LKB1 in this regulation. We show that mice with a hepatocyte-specific deletion of Lkb1 have higher levels of hepatic amino acid catabolism, driving gluconeogenesis. This effect was observed during both fasting and the postprandial period, identifying Lkb1 as a critical suppressor of postprandial hepatic gluconeogenesis. Hepatic Lkb1 deletion was associated with major changes in whole-body metabolism, leading to a lower lean body mass and, in the longer term, sarcopenia and cachexia, as a consequence of the diversion of amino acids to liver metabolism at the expense of muscle. Using genetic and pharmacological approaches, we identified the aminotransferases and specifically, Agxt as effectors of the suppressor function of Lkb1 in amino acid-driven gluconeogenesis. The present dataset is from the phosphoproteomic analysis of the refed mice in a study where a global quantitative analysis ( PXD013478 ) is also described in the same publication.
2020-12-01 | PXD019755 | Pride
Project description:The purpose of the experiment is to study the expression profiles variations upon the expression of the wild type isoform of LKB1 (STK11) in human lung carcinoma A459 cells. These cells are KRAS mutated and null for STK11. Cells were previously infected with the lentiviral construct pLenti-rtTA2-IRES-H2B-GFP doxycycline-inducible plasmid (obtained from S. Tenbaum, HG Palmer’s Lab Vall d´Hebron Institute of Oncology, VHIO) containing the human STK11wild type cDNA.
2020-06-11 | E-MTAB-8863 | biostudies-arrayexpress
Project description:Excessive glucose production in the liver is a key factor in the hyperglycemia observed in diabetes mellitus type 2. It is generally agreed to result from an increase in hepatic gluconeogenesis. Considerable attention has been devoted to the transcriptional regulation of key gluconeogenic enzymes, but much less is known about the regulation of amino-acid catabolism, which generates gluconeogenic substrates. Here, we highlight a novel role of LKB1 in this regulation. We show that mice with a hepatocyte-specific deletion of Lkb1 have higher levels of hepatic amino acid catabolism, driving gluconeogenesis. This effect was observed during both fasting and the postprandial period, identifying Lkb1 as a critical suppressor of postprandial hepatic gluconeogenesis. Hepatic Lkb1 deletion was associated with major changes in whole-body metabolism, leading to a lower lean body mass and, in the longer term, sarcopenia and cachexia, as a consequence of the diversion of amino acids to liver metabolism at the expense of muscle. Using genetic and pharmacological approaches, we identified the aminotransferases and specifically, Agxt as effectors of the suppressor function of Lkb1 in amino acid-driven gluconeogenesis. The present dataset is from the phosphoproteomic analysis of fasting mice in a study where a global quantitative analysis ( PXD013478 ) is also described in the same publication.
2020-12-01 | PXD019757 | Pride
Project description:Numerous studies have showed that mesenchymal-specific Lkb1 is sufficient for the development of PJS-like polyps in mice. However, the cellular origin and component of these Lkb1-associated polyps and underlying mechanisms remain elusive. In this present study, we generated tamoxifen-inducible Lkb1flox/flox;Myh11-Cre/ERT2 mice and performed scRNA-seq to investigate the cellular complexity of gastrointestinal polyps associated with PJS.
2024-02-09 | GSE253151 | GEO
Project description:Stomach and intestinal adult epithelia harbor stem cells that are responsible for their continuous regeneration. Stomach and intestinal stem cells differ in their differentiation program and in the gene repertoire that they express. We show that single adult Lgr5-positive stem cells, isolated from 3D cultured small intestinal organoids, require Cdx2 to maintain their intestinal identity and are converted cell-autonomously into stomach-pyloric stem cells in the absence of this transcription factor. In order to obtain Cdx2null intestinal stem cells carrying the Lgr5-EGFP marker, 5-6 days old small intestinal organoids generated from Cdx2-/fl/Lgr5-EGFP-Ires-CreERT2 mice were incubated with 1 µM of 4-hydroxytamoxifen in intestinal culture medium for 16h to activate the Cre recombinase. Controls were 4-hydroxytamoxifen-untreated small intestinal (Control SI) and stomach (Control Sto) organoids issued from mice with the same genotype. The organoids were dissociated and sorted for EGFPhi. Cdx2null, Control SI and Control Sto clonal organoids were generated and expanded from Lgr5-EGFPhi single cells in stomach specific culture medium (ENRWfg) and RNA was isolated for RNA-Seq analysis. Cdx2+ Stomach (Sto) organoids were generated by infection of the wild type stomach organoids with lentiviral stock expressing Cdx2. They were cultured in stomach medium (ENRWfg) and RNA was isolated for RNA-Seq analysis
2014-12-05 | E-GEOD-62784 | biostudies-arrayexpress
Project description:Background: Exceptional and extreme feeding behaviour makes the Burmese python (Python bivittatus) an interesting model to study physiological remodelling and metabolic adaptation in response to refeeding after prolonged starvation. In this study, we used transcriptome sequencing of five visceral organs during fasting as well as 24h and 48h after ingestion of a large meal to unravel the postprandial changes in Burmese pythons. We first used the pooled data to perform a de novo assembly of the transcriptome and supplemented this with a proteomic survey of enzymes in the plasma and gastric fluid. Results: We constructed a high-quality transcriptome with 34,423 transcripts of which 19,713 (57%) were annotated. Among highly expressed genes (FPKM>100 in one tissue) we found the transition from fasting to digestion was associated with differential expression of 43 genes in the heart, 206 genes in the liver, 114 genes in the stomach, 89 genes in the pancreas and 158 genes in the intestine. We interrogated the function of these genes to test previous hypotheses on the response to feeding. We also used the transcriptome to identify 314 secreted proteins in the gastric fluid of the python Conclusions: Digestion was associated with an upregulation of genes related to metabolic processes, and translational changes therefore appears to support the postprandial rise in metabolism. We identify stomach-related proteins from a digesting individual and demonstrate that the sensitivity of modern LC-MS/MS equipment allows the identification of gastric juice proteins that are present during digestion.
2018-10-24 | PXD006665 | Pride