PI3K inhibition activates SGK1 via a feedback loop to promote chromatin-based regulation of ER-dependent gene expression
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PROVIDER: PRJNA489456 | ENA |
REPOSITORIES: ENA
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Project description:The phosphoinositide 3-kinase (PI3K) pathway integrates extracellular stimuli to phosphorylate and activate key downstream effectors such as AKT and serum-and glucocorticoid-inducible kinase (SGK1). We have previously reported that the PI3K pathway regulates ER-dependent transcription in breast cancer through the phosphorylation of the epigenetic regulator KMT2D by AKT. Here, we provide new insights into how the PI3K pathway propagates its effects to control KMT2D and ER function via SGK1, another PI3K downstream effector. Specifically, we show that PI3K inhibition, via a negative feedback loop, activates SGK1 to promote chromatin-based regulation of ER-dependent gene expression. PI3K/AKT inhibitors activate ER, which subsequently promotes SGK1 transcription through direct binding to its promoter. Elevated SGK1, in turn, phosphorylates KMT2D, suppressing its function and altering the chromatin landscape to attenuate ER-dependent expression. Thus, we have determined that SGK1 regulates the chromatin landscape and ER-dependent transcription via the direct phosphorylation of KMT2D. These findings reveal an ER-SGK1-KMT2D signaling circuit aimed to attenuate ER response through a previously unknown role for SGK1 to program chromatin and ER transcriptional output.
2019-04-02 | GSE119522 | GEO
Project description: Not available
| S-EPMC6503687 | biostudies-literature
Project description:A balance between cell survival and apoptosis is essential for animal development. Although proper development involves multiple interactions between germ layers, little is known about the intercellular and intertissue signaling pathways that promote cell survival in neighboring or distant germ layers . We show that serum- and glucocorticoid-inducible kinase 1 (SGK1) promoted ectodermal cell survival during early Xenopus embryogenesis through a non-cell-autonomous mechanism. Dorsal depletion of SGK1 in Xenopus embryos resulted in shortened axes and reduced head structures with defective eyes, and ventral depletion led to defective tail morphologies. Although the gene encoding SGK1 was mainly expressed in the endoderm and dorsal mesoderm, knockdown of SGK1 caused excessive apoptosis in the ectoderm. SGK1-depleted ectodermal explants showed little or no apoptosis, suggesting non-cell-autonomous effects of SGK1 on ectodermal cells. Microarray analysis revealed that SGK1 knockdown increased the expression of genes encoding FADD and caspase-10, components of the death-inducing signaling complex (DISC). Inhibition of DISC function suppressed excessive apoptosis in SGK1-knockdown embryos. SGK1 acted through the transcription factor nuclear factor kappaB to stimulate production of bone morphogenetic protein 7 (BMP7), and overexpression of BMP7 in SGK1-knockdown embryos reduced the abundance of DISC components. We show that phosphoinositide 3-kinase (PI3K) functioned upstream of SGK1, thus revealing an endodermal and mesodermal pathway from PI3K to SGK1 to NF-kappaB that produces BMP7, which provides a survival signal to the ectoderm by decreasing DISC function. To identify genes whose expression levels are regulated by SGK1 in Xenopus development, we performed genome-wide analysis by using Affymetrix GeneChip oligonucleotide microarrays. We performed two independent experiments. For each microarray experiment, we radially injected control-morpholino or xSGK1-morpholinos into 4-cell embryos, cultured the embryos until stage 12, extracted total RNAs using Trizol (Invitrogen) and purified them on RNeasy columns (Qiagen). Synthesis of cDNA, in vitro transcription and biotin labeling of cRNA, and hybridization to the Xenopus laevis genome array (Affymetrix) were performed according to the Affymetrix protocol (Two-Cycle Target Labeling Assays). Hybridized arrays were scanned using an Affymetrix GeneChip Scanner. Scanned chip images were analyzed with GeneChip Operating Software (GCOS) v. 1.4.
2011-02-21 | E-GEOD-26381 | biostudies-arrayexpress
Project description:PRH/HHEX-Notch3 feedback loop drives cholangiocarcinoma
2018-12-28 | GSE124430 | GEO
Project description:PRH/HHEX-Notch3 feedback loop drives cholangiocarcinoma
2018-12-28 | GSE124429 | GEO
Project description:A balance between cell survival and apoptosis is essential for animal development. Although proper development involves multiple interactions between germ layers, little is known about the intercellular and intertissue signaling pathways that promote cell survival in neighboring or distant germ layers . We show that serum- and glucocorticoid-inducible kinase 1 (SGK1) promoted ectodermal cell survival during early Xenopus embryogenesis through a non-cell-autonomous mechanism. Dorsal depletion of SGK1 in Xenopus embryos resulted in shortened axes and reduced head structures with defective eyes, and ventral depletion led to defective tail morphologies. Although the gene encoding SGK1 was mainly expressed in the endoderm and dorsal mesoderm, knockdown of SGK1 caused excessive apoptosis in the ectoderm. SGK1-depleted ectodermal explants showed little or no apoptosis, suggesting non-cell-autonomous effects of SGK1 on ectodermal cells. Microarray analysis revealed that SGK1 knockdown increased the expression of genes encoding FADD and caspase-10, components of the death-inducing signaling complex (DISC). Inhibition of DISC function suppressed excessive apoptosis in SGK1-knockdown embryos. SGK1 acted through the transcription factor nuclear factor kappaB to stimulate production of bone morphogenetic protein 7 (BMP7), and overexpression of BMP7 in SGK1-knockdown embryos reduced the abundance of DISC components. We show that phosphoinositide 3-kinase (PI3K) functioned upstream of SGK1, thus revealing an endodermal and mesodermal pathway from PI3K to SGK1 to NF-kappaB that produces BMP7, which provides a survival signal to the ectoderm by decreasing DISC function.
2011-02-21 | GSE26381 | GEO
Project description:Analyses of RNAi-heterochromatin positive feedback loop in Tetrahymena
| PRJNA343227 | ENA
Project description:Defects in stress responses are important contributors in many chronic conditions including cancer, cardiovascular disease, diabetes, and obesity-driven pathologies like non-alcoholic steatohepatitis (NASH). Specifically, endoplasmic reticulum (ER) stress is linked with these pathologies and control of ER stress can ameliorate tissue damage. MicroRNAs have a critical role in regulating diverse stress responses including ER stress. Here we show that miR-494-3p plays a functional role during ER stress. ER stress inducers (tunicamycin and thapsigargin) robustly increase the expression of miR-494 in vitro in an ATF6 dependent manner. Surprisingly, miR-494 pretreatment dampens the induction and magnitude of ER stress in response to tunicamycin in endothelial cells. Conversely, inhibition of miR-494 increases ER stress de novo and amplifies the effects of ER stress inducers. Using Mass Spectrometry (TMT-MS) we identified many proteins that are downregulated by both tunicamycin and miR-494 in cultured human umbilical vein endothelial cells (HUVECs). Among these, we found 6 transcripts which harbor a putative miR-494 binding site. Our data indicates that ER stress driven miR-494 may act in a feedback inhibitory loop to dampen downstream ER stress signaling. We propose that RNA-based approaches targeting miR-494 or its targets may be attractive candidates for inhibiting ER stress dependent pathologies in human disease.
2021-09-09 | PXD019992 | Pride
Project description: Not available
| S-EPMC7337497 | biostudies-literature
Project description:Pre-operative progesterone intervention has been shown to confer a survival benefit to breast cancer patients independent of their progesterone receptor (PR) status, raising a question about how progesterone affects the outcome of PR-negative cells. Here, we identify up-regulation of a Serum- and glucocorticoid-regulated kinase gene, SGK1 and an N-Myc Downstream Regulated Gene 1, NDRG1, along with down-regulation of miR-29a and miR-101-1 targeting 3’UTR region of SGK1, to differential extents in a PR dependent manner in breast cancer cells. We further demonstrate a novel dual-phase transcriptional and post-transcriptional regulation of SGK1 in response to progesterone leading to up-regulation of a tumor metastasis suppressor gene, NDRG1, mediated by a set of AP-1 network genes. The NDRG1 further inactivates a set of kinases impeding the invasion and migration of breast cancer cells. In summary, we propose a model for the mode of action of progesterone in breast cancer deciphering the molecular basis of a randomized clinical trial studying the effect of progesterone in breast cancer with a potential to improve the prognosis of breast cancer patients for receiving pre-operative progesterone treatment.
2018-10-19 | E-MTAB-6742 | biostudies-arrayexpress