Nuclear GSK-3β and Oncogenic KRas Promote Aqp5+ Pancreatic Duct Stem Cell Expansion
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ABSTRACT:
PROVIDER: PRJNA717225 | ENA |
REPOSITORIES: ENA
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Project description:Intraductal papillary mucinous neoplasm (IPMN) represents the most commonly diagnosed precursor lesion of pancreatic ductal adenocarcinoma (PDA), however the cell-of-origin remains unclear. Herein, we show that pancreas-specific activation in mice of nuclear-targeted glycogen synthase kinase-3β and oncogenic KRasG12D leads to the loss of acinar cells, the expansion of ductal cells, and the rapid development of IPMN with low-grade dysplasia. RNA-sequencing identified the expression of several ductal stem cell lineage genes including the water channel AQP5. The Aqp5+ pancreatic ductal cell pool was proliferative, phenotypically distinct from mature pancreatic ductal cells, and deletion of AQP5 limited IPMN development. Significantly, Aqp5 is highly expressed in human IPMN along with GSK-3b suggesting that human preneoplastic lesions likely arise from the expansion of an Aqp5+ pancreatic ductal stem cell. Altogether, these data identify Aqp5+ ductal cells in the mouse and human pancreas as the likely cell-of-origin for IPMN.
2022-03-22 | GSE169618 | GEO
Project description:Intraductal papillary mucinous neoplasm (IPMN) represents one precursor lesion of pancreatic ductal adenocarcinoma (PDA), but the cell-of-origin remains unclear. Here we describe a new mouse model in which pancreas-specific Cre activation of a nuclear glycogen synthase kinase-3β transgene is combined with oncogenic KRas (referred to as KNGC). KNGC mice show accumulation of neoplastic ductal cells at 4-weeks that progressively develop into IPMN with low-grade dysplasia in advanced age. RNA-sequencing identified expression of several genes found in the terminal duct cell lineage including Agr2 and Aqp5. Interestingly, Aqp5, a water channel, was found to be required for the development of IPMN lesions in KNGC mice. Staining of human IPMN samples indicates that these preneoplastic lesions also arise from expansion of the terminal duct population. Altogether, these data highlight the utility of the KNGC model for understanding the biology of IPMN and potential utility in defining predictive biomarkers of IPMN – PDA development.
2022-03-22 | GSE153548 | GEO
Project description:Despite the prevalence of KRAS mutations in colorectal cancer, there is no K-Ras targeted therapies for these tumors and available treatment options are limited for metastatic disease. GSK-3β has been demonstrated to be a critically important kinase for survival and proliferation of K-Ras-depended pancreatic cancer cells. In this study we tested 9-ING-41, a small molecule inhibitor of GSK-3β, in patient-derived tumor organoid models of colorectal cancer. We demonstrated that addition of 9-ING-41 to the standard of care drugs 5-FU and oxaliplatin could significantly enhance inhibition of the growth of colorectal cancer cells harboring KRAS mutations. The results of the transcriptomic analysis support our findings of cell cycle arrest and DNA repair deficiency in 9-ING-41-treated colorectal cancer cells. Moreover, we found substantial similarity in the changes of transcriptomic profile after inhibition of GSK-3β and suppression of STK33, another critically important kinase for K-Ras-dependent cells. Overall, the results of this study provide a rationale for the inclusion of patients with mutant KRAS colorectal cancer in clinical studies of 9-ING-41 and other GSK-3 inhibitors.
2021-10-31 | GSE184125 | GEO
Project description:Nuclear GSK-3β and Oncogenic KRas Promote Expansion of Terminal Duct Cells and the Development of Intraductal Papillary Mucinous Neoplasm
| PRJNA643218 | ENA
Project description:Glycogen synthase kinase-3β (GSK-3β) has been recently identified as an important regulator of stem cell function. In vitro studies show that GSK-3β inhibition delays proliferation of human haematopoietic progenitor cells while increasing numbers of late dividing multipotent progenitors. Gene expression analysis revealed that GSK-3β inhibition modulates the expression of a subset of genes that are transcriptional targets for cytokines. GSK-3β inhibition antagonised down-regulation of genes encoding cyclin dependent kinase inhibitor p57 and a member of the growth arrest and DNA damage 45 family, GADD45B as well as up-regulation of cyclin D1 by cytokines, providing a possible mechanism for the BIO-induced delay in cell cycle progression. Surprisingly, inhibition of GSK-3β earlier shown to prevent β-catenin degradation and promote the nuclear accumulation of β-catenin was not sufficient to activate its transcriptional targets in haematopoietic stem cells. GSK-3β inhibition up-regulated the expression of a several positive regulators of stem cell function suppressed during cytokine-induced proliferation. The data supports a clinical role for GSK-3β inhibition to improve engraftment efficiency of ex vivo expanded stem cells.
2010-03-26 | GSE21073 | GEO
Project description:Mutations in KRAS occur in a variety of tumors of epithelial origin, driving the oncogenic phenotype.The NF-kB transcription factor pathway is important for oncogenic RAS to transform cells and to drive tumorigenesis in animal models. Recently TAK1, an upstream regulator of IKK which controls canonical NF-kB, was shown to be important for chemoresistance in pancreatic cancer and for regulating KRAS+ colorectal cancer cell growth and survival. Here we show that GSK-3alpha is upregulated by KRAS leading to interaction with TAK1 to stabilize the TAK1/TAB complex to promote IKK activity. Additionally, GSK-3alpha is required for promoting critical non-canonical NF-kB signaling in pancreatic cancer cells. Pharmacologic inhibition of GSK-3 suppresses growth of human pancreatic tumor explants, consistent with loss of expression of genes such as c-myc and TERT. These data identify GSK-3alpha as a key downstream effector of oncogenic RAS via its ability to coordinately regulate distinct NF-kB signaling pathways GSK-3 inhibition at 2 and 8 hours
2013-05-31 | E-GEOD-42559 | biostudies-arrayexpress
Project description:Mutations in KRAS occur in a variety of tumors of epithelial origin, driving the oncogenic phenotype.The NF-kB transcription factor pathway is important for oncogenic RAS to transform cells and to drive tumorigenesis in animal models. Recently TAK1, an upstream regulator of IKK which controls canonical NF-kB, was shown to be important for chemoresistance in pancreatic cancer and for regulating KRAS+ colorectal cancer cell growth and survival. Here we show that GSK-3alpha is upregulated by KRAS leading to interaction with TAK1 to stabilize the TAK1/TAB complex to promote IKK activity. Additionally, GSK-3alpha is required for promoting critical non-canonical NF-kB signaling in pancreatic cancer cells. Pharmacologic inhibition of GSK-3 suppresses growth of human pancreatic tumor explants, consistent with loss of expression of genes such as c-myc and TERT. These data identify GSK-3alpha as a key downstream effector of oncogenic RAS via its ability to coordinately regulate distinct NF-kB signaling pathways
2013-05-31 | GSE42559 | GEO
Project description:To analyze the roles of GSK-3β in podocytes, GSK-3β knockdown lentivirus by Clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein (Cas)9 was applied to establish stable cell lines. Phosphoproteome and proteome evaluation was conducted using TMT labeled LC-MS/MS technologies.
2021-09-10 | PXD024543 | Pride
Project description:9-ING-41, a small molecule inhibitor of GSK-3β, potentiates the effects of chemotherapy in KRAS mutated colorectal cancer
| PRJNA763229 | ENA
Project description:Nuclear myosin 1c (NM1) mediates RNA polymerase I (pol I) transcription activation and cell cycle progression by facilitating PCAF-mediated H3K9 acetylation, but the molecular mechanism by which NM1 is regulated remains unclear. Here, we report that at early G1 the glycogen synthase kinase (GSK) 3β phosphorylates and stabilizes NM1, allowing for NM1 association with the chromatin. Genomic analysis by ChIP-Seq showed that this mechanism occurs on the rDNA as active GSK3β selectively occupies the gene. ChIP assays and transmission electron microscopy in GSK3β-/- mouse embryonic fibroblasts indicated that at G1 rRNA synthesis is suppressed due to decreased H3K9 acetylation leading to a chromatin state incompatible with transcription. We found that GSK3β directly phosphorylates the endogenous NM1 on a single serine residue (Ser-1020) located within the NM1 C-terminus. In G1 this phosphorylation event stabilizes NM1 and prevents NM1 polyubiquitination by the E3 ligase UBR5 and proteasome-mediated degradation. We conclude that GSK3β-mediated phosphorylation of NM1 is required for pol I transcription activation. Examination of GSK3beta with the genome in mouse embryonic fibroblasts
2014-05-02 | E-GEOD-57153 | biostudies-arrayexpress