KRAS is required for placenta development
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1017497 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26065816.fastq.gz | Fastqsanger.gz | |||
| SRR26065817.fastq.gz | Fastqsanger.gz |
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Project description:Besides its well-known roles in cancer, KRAS is important for embryogenesis, as its absence causes embryonic lethality. The precise mechanisms underlying the developmental functions of KRAS is still incompletely characterized. To address this issue, we analyzed Kras-/- mouse embryos. We observed that Kras-/- embryos show a lethality that starts around E13.5. Interestingly, a placental phenotype was observed in Kras-/- embryos. This phenotype was associated with a small placental size, and a marked decrease in glycogen trophoblast cells. It was related to the presence of hypoglycaemia and hypoxia in Kras-/- embryos. Thus, our study reveals hidden functions of KRAS4. Importantly, it identifies for the first time a role for KRAS in the differentiation process of a specific cell type and the biological defects caused by a loss of KRAS.
2023-09-17 | GSE243258 | GEO
Project description:Previous studies in the mouse indicated that Arid3a plays a critical role in the first cell fate decision required for generation of trophectoderm (TE). Here, we demonstrate that Arid3a is widely expressed during mouse and human placentation and essential for early embryonic viability. Arid3a is located within trophoblast giant cells and other trophoblast-derived cell subtypes in the junctional and labyrinth zones of the placenta. Conventional Arid3a knockout embryos suffer restricted intrauterine growth with sever defects in placental structural organization. Arid3a null placentas show aberrant expression of subtype-specific markers as well as significant alteration in inflammatory response-related genes, cytokines and chemokines. We provide evidence that BMP4-mediated induction of trophoblast stem (TS)-like cells from human induced pluripotent (iPS) stem cells results in ARID3A upregulation and cytoplasmic to nuclear translocation. Overexpression of ARID3A in human iPS and BMP4-mediated TS-like cells up-regulated TE markers, whereas pluripotent markers were down-regulated. Our results indicate that the roles of Arid3a are conserved and essential for mammalian placental development through regulation of both intrinsic and extrinsic developmental programs. Placentas of E10.5 and E11.5 wild type (WT) and Arid3a-/- mice were generated by deep sequencing, using Illumina
2016-07-01 | E-GEOD-79638 | biostudies-arrayexpress
Project description:Previous studies in the mouse indicated that Arid3a plays a critical role in the first cell fate decision required for generation of trophectoderm (TE). Here, we demonstrate that Arid3a is widely expressed during mouse and human placentation and essential for early embryonic viability. Arid3a is located within trophoblast giant cells and other trophoblast-derived cell subtypes in the junctional and labyrinth zones of the placenta. Conventional Arid3a knockout embryos suffer restricted intrauterine growth with sever defects in placental structural organization. Arid3a null placentas show aberrant expression of subtype-specific markers as well as significant alteration in inflammatory response-related genes, cytokines and chemokines. We provide evidence that BMP4-mediated induction of trophoblast stem (TS)-like cells from human induced pluripotent (iPS) stem cells results in ARID3A upregulation and cytoplasmic to nuclear translocation. Overexpression of ARID3A in human iPS and BMP4-mediated TS-like cells up-regulated TE markers, whereas pluripotent markers were down-regulated. Our results indicate that the roles of Arid3a are conserved and essential for mammalian placental development through regulation of both intrinsic and extrinsic developmental programs.
2016-07-01 | GSE79638 | GEO
Project description:Cancers with activating mutations of KRAS show a high prevalence and poor prognosis but remain intractable, requiring innovative strategies to overcome the poor targetability of KRAS. Here, we report that KRAS expression was post-translationally up-regulated through the deubiquitination of KRAS protein when the scaffolding function of NDRG3 (N-Myc downstream regulated gene 3) promoted specific interaction between KRAS and a deubiquitinating enzyme, USP9X. In KRAS-mutant pancreatic or lung cancer cells KRAS protein expression, downstream signaling, and cell growth were highly dependent on NDRG3. In conditional KrasG12D knock-in mouse models of pancreatic ductal adenocarcinoma (PDAC), Ndrg3 depletion abolished Kras protein expression in pancreas, and suppressed pancreatic intraepithelial neoplasia (PanIN) formation. Mechanistically, KRAS protein bound to the C-terminal serine/threonine-rich region of NDRG3, subsequently going through the deubiquitination by USP9X recruited to the complex. This interaction could be disrupted in a dominant-negative manner by a C-terminal NDRG3 fragment that can bind KRAS but is defective in USP9X binding, highly suppressing the KRAS protein expression and KRAS-driven cell growth. In summary, KRAS-driven cancer development critically depends on the deubiquitination of KRAS protein mediated by USP9X/NDRG3, and KRAS-addicted cancers could be effectively targeted by inhibiting the KRAS-NDRG3 interaction.
2025-05-07 | PXD052379 | Pride
Project description:Cancers with activating mutations of KRAS show a high prevalence and poor prognosis but remain intractable, requiring innovative strategies to overcome the poor targetability of KRAS. Here, we report that KRAS expression was post-translationally up-regulated through the deubiquitination of KRAS protein when the scaffolding function of NDRG3 (N-Myc downstream regulated gene 3) promoted specific interaction between KRAS and a deubiquitinating enzyme, USP9X. In KRAS-mutant pancreatic or lung cancer cells KRAS protein expression, downstream signaling, and cell growth were highly dependent on NDRG3. In conditional KrasG12D knock-in mouse models of pancreatic ductal adenocarcinoma (PDAC), Ndrg3 depletion abolished Kras protein expression in pancreas, and suppressed pancreatic intraepithelial neoplasia (PanIN) formation. Mechanistically, KRAS protein bound to the C-terminal serine/threonine-rich region of NDRG3, subsequently going through the deubiquitination by USP9X recruited to the complex. This interaction could be disrupted in a dominant-negative manner by a C-terminal NDRG3 fragment that can bind KRAS but is defective in USP9X binding, highly suppressing the KRAS protein expression and KRAS-driven cell growth. In summary, KRAS-driven cancer development critically depends on the deubiquitination of KRAS protein mediated by USP9X/NDRG3, and KRAS-addicted cancers could be effectively targeted by inhibiting the KRAS-NDRG3 interaction.
2025-05-06 | PXD051954 | Pride
Project description:That mutational activation of Kras and inactivation of p16 are two signature genetic alterations required for development of PDAC. To elucidate the downstream pathways activated by oncogenic Kras and inactivated p16 in human pancreatic tumorigenesis, we profiled gene expression in HPNE/Kras/shp16 and HPNE/Kras cells using cDNA microarray analysis.
2016-11-03 | GSE89422 | GEO
Project description:Accumulation of genetic mutations is thought to be a primary cause of cancer. However, a set of genetic mutations sufficient for cancer development remains unclear in most cancers, including pancreatic cancer. Here, we examined the effect of in vivo reprogramming on Kras-induced cancer development. We first demonstrate that Kras and p53 mutations are insufficient to induce activation of ERK signaling and cancer development in the pancreas. We next show that short transient expression of reprogramming factors (1-3 days) in pancreatic acinar cells results in repression of acinar cell enhancers and reversible loss of acinar cell properties. Notably, the transient expression of reprogramming factors in Kras mutant mice is sufficient to induce robust and persistent activation of ERK signaling in acinar cells and rapid formation of pancreatic ductal adenocarcinoma (PDAC). In contrast, forced expression of acinar cell-related transcription factors inhibits pancreatitis-induced activation of ERK signaling and development of precancerous lesions in Kras-mutated acinar cells.
2018-05-16 | GSE100841 | GEO
Project description:In vivo reprogramming drives Kras-induced cancer development
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Project description:Accumulation of genetic mutations is thought to be a primary cause of cancer. However, a set of genetic mutations sufficient for cancer development remains unclear in most cancers, including pancreatic cancer. Here, we examined the effect of in vivo reprogramming on Kras-induced cancer development. We first demonstrate that Kras and p53 mutations are insufficient to induce activation of ERK signaling and cancer development in the pancreas. We next show that short transient expression of reprogramming factors (1-3 days) in pancreatic acinar cells results in repression of acinar cell enhancers and reversible loss of acinar cell properties. Notably, the transient expression of reprogramming factors in Kras mutant mice is sufficient to induce robust and persistent activation of ERK signaling in acinar cells and rapid formation of pancreatic ductal adenocarcinoma (PDAC). In contrast, forced expression of acinar cell-related transcription factors inhibits pancreatitis-induced activation of ERK signaling and development of precancerous lesions in Kras-mutated acinar cells.
2018-05-16 | GSE100840 | GEO
Project description:Oncogenic KRAS signaling is required for tumor survival in cancers that harbor KRAS mutations. We recently performed a genome-scale expression screen to identify genes that bypass KRAS dependency. Here we demonstrate that the developmental transcription factor LHX9 rescues KRAS suppression in vitro and xenograft models. Furthermore, LHX9 decreases cell sensitivity to KRASG12C and MEK1/2 inhibitors. LHX9 promotes transcriptional changes associated with KRAS. Importantly, YAP1 upregulation by LHX9 is required for the rescue of KRAS suppression. Together we identify LHX9 as a YAP1 transcriptional regulator that permits KRAS-dependent cells to proliferate without KRAS expression.
2018-12-01 | GSE116822 | GEO