PI3K inhibition activates SGK1 via a feedback loop to promote chromatin-based regulation of ER-dependent gene expression
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ABSTRACT:
PROVIDER: PRJNA489456 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7789370_1.fastq.gz | Fastqsanger.gz | |||
| SRR7789370_2.fastq.gz | Fastqsanger.gz | |||
| SRR7789369_1.fastq.gz | Fastqsanger.gz | |||
| SRR7789369_2.fastq.gz | Fastqsanger.gz | |||
| SRR8627680.fastq.gz | Fastqsanger.gz |
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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:The PI3K pathway integrates extracellular stimuli to phosphorylate effectors such as AKT and serum-and-glucocorticoid-regulated kinase (SGK1). We have previously reported that the PI3K pathway regulates estrogen receptor (ER)-dependent transcription in breast cancer through the phosphorylation of the lysine methyltransferase KMT2D by AKT. Here, we show that PI3Kα inhibition, via a negative-feedback loop, activates SGK1 to promote chromatin-based regulation of ER-dependent transcription. PI3K/AKT inhibitors activate ER, which promotes SGK1 transcription through direct binding to its promoter. Elevated SGK1, in turn, phosphorylates KMT2D, suppressing its function, leading to a loss of methylation of lysine 4 on histone H3 (H3K4) and a repressive chromatin state at ER loci to attenuate ER activity. Thus, 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 role for SGK1 to program chromatin and ER transcriptional output.
| 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: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:Autophagy degrades cytoplasmic cargo by its delivery to lysosomes within double membrane autophagosomes. Synthesis of the phosphoinositide PI(3)P by the autophagic class III phosphatidylinositol-3 kinase complex I (PI3KC3-C1) and conjugation of ATG8/LC3 proteins to phagophore membranes by the ATG12-ATG5-ATG16L1 (E3) complex are two critical steps in autophagosome biogenesis, connected by WIPI2. Here, we present a complete reconstitution of these events. On giant unilamellar vesicles (GUVs), LC3 lipidation is strictly dependent on the recruitment of WIPI2 that in turn depends on PI(3)P. Ectopically targeting E3 to membranes in the absence of WIPI2 is insufficient to support LC3 lipidation, demonstrating that WIPI2 allosterically activates the E3 complex. PI3KC3-C1 and WIPI2 mutually promote the recruitment of each other in a positive feedback loop. When both PI 3-kinase and LC3 lipidation reactions were performed simultaneously, positive feedback between PI3KC3-C1 and WIPI2 led to rapid LC3 lipidation with kinetics similar to that seen in cellular autophagosome formation.
| 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
Project description:Phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway activation contributes to mantle cell lymphoma (MCL) pathogenesis and drug resistance. However, the use of mTOR inhibitors as single agents have shown limited clinical efficacy in relation with drug activation of feedback loops. Selective PI3K inhibition or dual PI3K/mTOR catalytic inhibition are different therapeutic approaches developed to achieve effective pathway blockage. Here, we evaluated the antitumor activity of a mTOR inhibitor, a pan-PI3K inhibitor and a dual PI3K/mTOR inhibitor in primary MCL cells. We found that dual PI3K/mTOR inhibitor modulated angiogenesis, tumor invasiveness and cytokine signaling compared to a mTOR inhibitor and a pan-PI3K inhibitor in MCL. We used microarrays to compare the effect of these three compounds in MCL and identified distinct classes of down-regulated genes modulated by each compound. Global RNA expression in primary cells from two MCL patients treated with a mTOR inhibitor, a pan-PI3K inhibitor and a dual PI3K/mTOR inhibitor for 8 hours
2013-12-14 | E-GEOD-53309 | biostudies-arrayexpress
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2022-12-15 | GSE219283 | GEO
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