PP2A dependent modulation of c-Myc and p21 leads to differentiation and cell cycle control in Acute Myeloid Leukemia
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE148018 | GEO | 2022/03/16
REPOSITORIES: GEO
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Project description:Phosphatase PP2A expression level is positively correlated to the clinical severity of systemic lupus erythematosus (SLE) and IL17A cytokine overproduction, indicating a potential role of PP2A in controlling TH17 differentiation and inflammation. By generating a mouse strain with the ablation of the catalytic subunit α of PP2A in peripheral mature T cells (PP2A cKO), we provide evidence here that PP2A complex is essential in TH17 differentiation. Hence, PP2A cKO mice exhibited a selective reduction of TH17 cell numbers and an attenuated disease severity in an experimental autoimmune encephalomyelitis (EAE) model. Importantly, PP2A deficiency ablated c-terminal phosphorylation of SMAD2 whereas increased c-terminal phosphorylation of SMAD3. Through direct binding to and regulating the activity of RORγt, the phosphorylational changes of these R-SMADs subsequently reduced Il17a transcription. Finally, PP2A inhibitors recapitulated the phenotype of PP2A cKO mice, i.e., inhibiting TH17 differentiation and protecting mice from EAE. Together, the current study proves that phosphatase PP2A is essential for TH17 differentiation, and inhibition of PP2A could be a possible therapeutic approach for the controlling of TH17-driven autoimmune diseases.
2018-09-13 | GSE119836 | GEO
Project description:Protein phosphatase 2A (PP2A), a serine/threonine phosphatase, has been shown to control T cell function. We found that in vitro activated B cells and B cells from various lupus-prone mice and patients with systemic lupus erythematosus display increased PP2A activity. To understand the contribution of PP2A to B cell function, we generated a Cd19CrePpp2r1aflox/flox (flox/flox) mouse which lacks functional PP2A only in B cells. Flox/flox mice displayed reduced spontaneous germinal center formation and decreased responses to T-dependent and T-independent antigens while their B cells responded poorly in vitro to stimulation with an anti-CD40 antibody or CpG in the presence of IL-4. Transcriptome and metabolome studies revealed altered NAD and purine/pyrimidine metabolism and increased expression of purine nucleoside phosphorylase in PP2A-deficient B cells. Our results demonstrate that PP2A is required for optimal B cell function and may contribute to increased B cell activity in systemic autoimmunity.
2020-02-04 | GSE144700 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE38565: The yeast PP2A-CDC55 phosphatase regulates the transcriptional response to hyperosmolarity stress by regulating Msn2 and Msn4 [Time course 1] GSE42033: The yeast PP2A-CDC55 phosphatase regulates the transcriptional response to hyperosmolarity stress by regulating Msn2 and Msn4 [Time course 2] Refer to individual Series
2012-11-06 | E-GEOD-42034 | biostudies-arrayexpress
Project description:We evaluated the effects of suppressing MAP4K4 on transcriptome and YAP1 pathway based on the observation that partial suppression of MAP4K4 leads to transformation through activation of YAP1. Mutations and deletions involving subunits of the serine-threonine phosphatase PP2A occur in a broad range of human cancers, and partial loss of PP2A function contributes to cell transformation. In particular, displacement of regulatory B subunits by the viral oncoprotein SV40 small-t antigen (ST) or mutation or deletion of PP2A subunits alters the abundance and types of PP2A complexes in cells and induces cell transformation in human cells. Here we show that ST not only displaces common PP2A B subunits but also promotes PP2A A-C subunit interactions with a set of alternative B subunits (B’’’, striatins) that are components of the Striatin-interacting phosphatase and kinase (STRIPAK) complex. We found that members of the STRIPAK complex are required for ST-PP2A induced cell transformation. PP2A interacts with and dephosphorylates the STRIPAK-associated kinase MAP4K4, which induces cell transformation in part through the regulation of the Hippo pathway effector YAP1. These observations identify an unanticipated role of MAP4K4 in transformation and show that the STRIPAK complex plays a key role in defining PP2A specificity and activity.
2019-12-01 | GSE118272 | GEO
Project description:RAS-mediated human cell transformation requires inhibition of the tumor suppressor Protein Phosphatase 2A (PP2A). Both RAS and PP2A mediate their effects by phosphoregulation, but phosphoprotein targets and cellular processes in which RAS and PP2A activities converge in human cancers have not been systematically analyzed. Here, based on mass spectrometry phosphoproteome data we discover that phosphosites co-regulated by RAS and PP2A are enriched on proteins involved in epigenetic gene regulation. As examples, RAS and PP2A co-regulate the same phosphorylation sites on HDAC1/2, KDM1A, MTA1/2, RNF168 and TP53BP1. Mechanistically, we validate co-regulation of NuRD chromatin repressor complex by RAS and PP2A. Consistent with their known synergistic effects in cancer, RAS activation and PP2A inhibition resulted in epigenetic reporter de-repression and activation of oncogenic transcription. Notably, transcriptional de-repression by PP2A inhibition was associated with increased euchromatin and decrease in global DNA methylation. Further, targeting of RAS- and PP2A-regulated epigenetic proteins decreased viability of KRAS-mutant human lung cancer cells. Collectively the results indicate that epigenetic protein complexes involved in oncogenic gene expression constitute a significant point of convergence for RAS hyperactivity and PP2A inhibition in cancer. Further, this work provides a resource for future studies focusing on phosphoregulation as a previously unappreciated layer of regulation of epigenetic gene regulation in cancer, and in other RAS/PP2A-regulated cellular processes.
2023-02-06 | GSE220590 | GEO
Project description:RAS-mediated human cell transformation requires inhibition of the tumor suppressor Protein Phosphatase 2A (PP2A). Both RAS and PP2A mediate their effects by phosphoregulation, but phosphoprotein targets and cellular processes in which RAS and PP2A activities converge in human cancers have not been systematically analyzed. Here, based on mass spectrometry phosphoproteome data we discover that phosphosites co-regulated by RAS and PP2A are enriched on proteins involved in epigenetic gene regulation. As examples, RAS and PP2A co-regulate the same phosphorylation sites on HDAC1/2, KDM1A, MTA1/2, RNF168 and TP53BP1. Mechanistically, we validate co-regulation of NuRD chromatin repressor complex by RAS and PP2A. Consistent with their known synergistic effects in cancer, RAS activation and PP2A inhibition resulted in epigenetic reporter de-repression and activation of oncogenic transcription. Notably, transcriptional de-repression by PP2A inhibition was associated with increased euchromatin and decrease in global DNA methylation. Further, targeting of RAS- and PP2A-regulated epigenetic proteins decreased viability of KRAS-mutant human lung cancer cells. Collectively the results indicate that epigenetic protein complexes involved in oncogenic gene expression constitute a significant point of convergence for RAS hyperactivity and PP2A inhibition in cancer. Further, this work provides a resource for future studies focusing on phosphoregulation as a previously unappreciated layer of regulation of epigenetic gene regulation in cancer, and in other RAS/PP2A-regulated cellular processes.
2023-02-06 | GSE220592 | GEO
Project description:RAS-mediated human cell transformation requires inhibition of the tumor suppressor Protein Phosphatase 2A (PP2A). Both RAS and PP2A mediate their effects by phosphoregulation, but phosphoprotein targets and cellular processes in which RAS and PP2A activities converge in human cancers have not been systematically analyzed. Here, based on mass spectrometry phosphoproteome data we discover that phosphosites co-regulated by RAS and PP2A are enriched on proteins involved in epigenetic gene regulation. As examples, RAS and PP2A co-regulate the same phosphorylation sites on HDAC1/2, KDM1A, MTA1/2, RNF168 and TP53BP1. Mechanistically, we validate co-regulation of NuRD chromatin repressor complex by RAS and PP2A. Consistent with their known synergistic effects in cancer, RAS activation and PP2A inhibition resulted in epigenetic reporter de-repression and activation of oncogenic transcription. Notably, transcriptional de-repression by PP2A inhibition was associated with increased euchromatin and decrease in global DNA methylation. Further, targeting of RAS- and PP2A-regulated epigenetic proteins decreased viability of KRAS-mutant human lung cancer cells. Collectively the results indicate that epigenetic protein complexes involved in oncogenic gene expression constitute a significant point of convergence for RAS hyperactivity and PP2A inhibition in cancer. Further, this work provides a resource for future studies focusing on phosphoregulation as a previously unappreciated layer of regulation of epigenetic gene regulation in cancer, and in other RAS/PP2A-regulated cellular processes.
2023-02-06 | GSE220591 | GEO
Project description:As a serine/threonine phosphatase, protein phosphatase 2A (PP2A) is essential in numerous physiological processes. Our previously study confirmed PP2A dysfunction can cause azoospermia by generating catalytic subunit of PP2A (Ppp2ca) conditional knockout (CKO) in C57BL/6J mice. Here, we further explored the possible mechanisms by focusing on meiosis initiation and spermatogenesis. The deficiency of Ppp2ca in germ cells conspicuously disturbed spermatogonial differentiation and lead to pachytene arrest, accompanied by defects in programmed double-strand break (DSB) repair and meiotic sex chromosome inactivation (MSCI). Furthermore, Ppp2ca-deficient spermatocytes exhibited abnormal agglutination and cohesion complex degradation of chromosome, probably contributing to pachytene arrest. Our study demonstrates the irreplaceable role of PP2A in spermatogenesis and provide more evidences on azoospermia etiology.
2021-12-01 | GSE181132 | GEO
Project description:The yeast PP2A-Cdc55 Serine/Threonine phosphatase regulates transcription under certain conditions. It is required for full activation of the environmental stress response mediated by the transcription factors Msn2 and Msn4. PP2A-Cdc55 contributes to sustained nuclear accumulation of Msn2 and Msn4 and extended chromatin recruitment under stress conditions such as hyperosmolarity stress. Transcript profiles of Msn2 and Msn4 double mutants are similar to cdc55 and the corresponding triple mutants. This argues for a Msn2/4 specific function of PP2A-Cdc55. Time course of 10 20 and 30 minutes hyperosmolarity treated yeast cells of wild type (W303), msn2msn4, cdc55, msn2msn5cdc55 genetic background.
2012-06-07 | E-GEOD-38565 | biostudies-arrayexpress
Project description:Gene expression by RNA Polymerase II (RNAPII) is tightly controlled by Cyclin-dependent kinases (CDKs) at discrete checkpoints during the transcription cycle. The RNAPII pausing checkpoint, engaged after transcription initiation, is controlled by CDK9 to regulate transcription in metazoans. We discovered that CDK9-mediated RNAPII pause-release is functionally opposed by a protein phosphatase 2A (PP2A) complex. PP2A dynamically competes for key CDK9 substrates, DSIF and RNAPII-CTD, and is recruited to transcription pausing sites by the Integrator complex subunit INTS6. INTS6 depletion confers resistance to CDK9 inhibition in a variety of normal and tumor cell lines. Loss of INTS6 abolishes the Integrator-PP2A association leading to unrestrained CDK9 activity, which amplifies transcriptional responses. Pharmacological PP2A activation synergizes with CDK9 inhibition to kill MLL-rearranged leukemias and solid tumors and provide therapeutic benefit in vivo. These data demonstrate that f inely-tuned gene expression relies on the balance of kinase and phosphatase activity at the pausing checkpoint.
2021-05-23 | GSE163803 | GEO