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PPM1D suppresses p53-dependent transactivation and cell death by inhibiting the HRI-eIF2alpha-ATF4 pathway.

ABSTRACT: PPM1D suppresses p53-dependent transactivation and cell death by inhibiting the HRI-eIF2alpha-ATF4 pathway.

PROVIDER: PRJNA789876 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR17263507.fastq.gz	Fastqsanger.gz
	SRR17263508.fastq.gz	Fastqsanger.gz
	SRR17263509.fastq.gz	Fastqsanger.gz
	SRR17263510.fastq.gz	Fastqsanger.gz
	SRR17263511.fastq.gz	Fastqsanger.gz

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PPM1D suppresses p53-dependent transactivation and cell death by inhibiting the HRI-eIF2alpha-ATF4 pathway [RNA-seq]

Project description:The p53 transcription factor is a master regulator of cellular stress responses restrained by repressors such as MDM2 and the phosphatase PPM1D. Activation of p53 with pharmacological inhibitors of its repressors is being tested in clinical trials for cancer therapy, but efficacy has been limited by poor induction of tumor cell death. We demonstrate that dual inhibition of MDM2 and PPM1D induces cell death in multiple cancer cell types via amplification of the p53 transcriptional program through the eIF2alpha -ATF4 pathway. PPM1D inhibition induces phosphorylation of eIF2alpha, ATF4 accumulation, and ATF4-dependent enhancement of p53-dependent transactivation upon MDM2 inhibition. Dual inhibition of p53 repressors depletes heme and induces HRI-dependent eIF2alpha phosphorylation. Pharmacological induction of eIF2alpha phosphorylation synergizes with MDM2 inhibition to induce cell death and halt tumor growth in mice. These results demonstrate that PPM1D inhibits both the p53 network and the integrated stress response controlled by eIF2alpha, with clear therapeutic implications.

2022-11-01 | GSE191148 | GEO

PPM1D suppresses p53-dependent transactivation and cell death by inhibiting the HRI-eIF2alpha-ATF4 pathway [ChIP-seq]

2022-09-01 | GSE191149 | GEO

PPM1D suppresses p53-dependent transactivation and cell death by inhibiting the HRI-eIF2alpha-ATF4 pathway [ChIP-seq]

Project description:PPM1D suppresses p53-dependent transactivation and cell death by inhibiting the HRI-eIF2alpha-ATF4 pathway [ChIP-seq]

| PRJNA789879 | ENA

PPM1D suppresses p53-dependent transactivation and cell death by inhibiting the HRI-eIF2alpha-ATF4 pathway [RNA-seq]

Project description:PPM1D suppresses p53-dependent transactivation and cell death by inhibiting the HRI-eIF2alpha-ATF4 pathway [RNA-seq]

| PRJNA789880 | ENA

PPM1D suppresses p53-dependent transactivation and cell death by inhibiting the HRI-eIF2alpha-ATF4 pathway.

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-09-01 | GSE191150 | GEO

HRI activates ATF4 to promote BCL11A transcription and fetal hemoglobin silencing [ChIP-seq]

Project description:Through a CRISPR-Cas9 guided loss-of-function screen in human erythroid cells we identified transcription factor ATF4, a known HRI-regulated protein, as a novel γ-globin repressor. ATF4 binds to a BCL11A enhancer to augment promoter contacts, stimulates BCL11A transcription to repress γ-globin expression. Notably, mice deficient for HRI displayed normal Bcl11a levels, suggesting species selective regulation that we explain here by demonstrating that the analogous ATF4 motif at the murine Bcl11a enhancer is largely dispensable. This illustrates potential limits of commonly used murine models of globin gene regulation.

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HRI activates ATF4 to promote BCL11A transcription and fetal hemoglobin silencing [Capture-C]

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Intricate coupling between the transactivation and basic-leucine zipper domains governs the CK2-dependent phosphorylation of ATF4

Project description:Most transcription factors possess at least one long intrinsically disordered transactivation domain that binds to a variety of co-activators and co-repressors and plays a key role in modulating the transcriptional activity. Despite the crucial importance of these mechanisms, the structural and functional basis of transactivation domain in yet poorly understood. Here, we focused on ATF4/CREB-2, an essential transcription factor for cellular stress adaptation. We found that the N-terminal region of the transactivation domain is involved in transient long-range interactions with the basic-leucine zipper domain. In vitro phosphorylation assays with the protein kinase CK2 show that the presence of the basic-leucine zipper domain is required for optimal phosphorylation of the transactivation domain. This study uncovers the intricate coupling existing between the transactivation and basic-leucine zipper domains of ATF4 and highlights its potential functional relevance.

2023-03-11 | PXD029704 | Pride

A Novel Squaramide Derivative, HR-19011, Induces the Integrated Stress Response via the HRI-eIF2α-ATF4 Pathway, Effectively Inhibiting Hematologic Malignancies

Project description:We investigated the therapeutic potential and mechanisms of HR-19011, a novel eIF2α phosphorylation inducer, with a focus on its effects on the integrated stress response (ISR) pathway and cell cycle regulation in K562 cells. Our findings revealed that HR-19011 exerts its anticancer effects primarily through the activation of heme-regulated inhibitor (HRI), leading to the phosphorylation of eukaryotic translation initiation factor 2 (eIF2)α, the induction of ISR signaling, and subsequent G1/S cell cycle arrest. RNA sequencing analysis further highlighted significant changes in gene expression associated with the ISR pathway, particularly those involving the key components, activating transcription factor 4 (ATF4) and CHOP, underscoring the specific targeting of HRI by HR-19011. Additionally, HR-19011 suppressed the mTORC1 pathway, a critical regulator of cell growth and metabolism, through the downregulation of components such as phosphorylated (p)-S6K and p-4EBP1, mediated by ATF4 and CHOP. In vivo studies demonstrated that HR-19011 effectively inhibited tumor growth in a K562 xenograft model, without significant toxicity, and its broad efficacy across various hematologic malignancies further suggests its potential as a versatile anticancer agent. Our findings position HR-19011 as a promising candidate for targeting the HRI-eIF2α axis in cancer treatment, warranting further investigation and optimization for clinical application.

2025-04-21 | GSE288955 | GEO

Gene expression profile at Ptpmt1 cardiomyocytes-specific Knockout mcie, Eif2a mutant mice, Gcn2 Knockout mice, and Hri Knockout mice

Project description:To study the mitochondrial stress response HRI-eIF2a-ATF4 signaling pathway in mitochondrial cardiomyopathy , we generated Ptpmt1 cardiomyocytes-specific Knockout mcie, Eif2a mutant mcie, Gcn2 Knockout mcie, and Hri Knockout mcie

2022-04-21 | GSE201042 | GEO

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