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Wild-type P53 proteolytic inactivation by asparagine endopeptidase promotes glioblastoma progression

ABSTRACT: Wild-type P53 proteolytic inactivation by asparagine endopeptidase promotes glioblastoma progression

PROVIDER: PRJNA414419 | ENA |

REPOSITORIES: ENA

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Wild-type P53 proteolytic inactivation by asparagine endopeptidase promotes glioblastoma progression

Project description:A comparison of expression changes between AEP RNAi and U87 control cell lines

2019-10-01 | GSE104806 | GEO

Role of Asparagine Endopeptidase in Mediating Wild-Type p53 Inactivation of Glioblastoma.

Project description:BackgroundIsocitrate dehydrogenase wild-type (WT) glioblastoma (GBM) accounts for 90% of all GBMs, yet only 27% of isocitrate dehydrogenase WT-GBMs have p53 mutations. However, the tumor surveillance function of WT-p53 in GBM is subverted by mechanisms that are not fully understood.MethodsWe investigated the proteolytic inactivation of WT-p53 by asparaginyl endopeptidase (AEP) and its effects on GBM progression in cancer cells, murine models, and patients' specimens using biochemical and functional assays. The sera of healthy donors (n = 48) and GBM patients (n = 20) were examined by enzyme-linked immunosorbent assay. Furthermore, effects of AEP inhibitors on GBM progression were evaluated in murine models (n = 6-8 per group). The statistical significance between groups was determined using two-tailed Student t tests.ResultsWe demonstrate that AEP binds to and directly cleaves WT-p53, resulting in the inhibition of WT-p53-mediated tumor suppressor function in both tumor cells and stromal cells via extracellular vesicle communication. High expression of uncleavable p53-N311A-mutant rescue AEP-induced tumorigenesis, proliferation, and anti-apoptotic abilities. Knock down or pharmacological inhibition of AEP reduced tumorigenesis and prolonged survival in murine models. However, overexpression of AEP promoted tumorigenesis and shortened the survival time. Moreover, high AEP levels in GBM tissues were associated with a poor prognosis of GBM patients (n = 83; hazard ratio = 3.94, 95% confidence interval = 1.87 to 8.28; P < .001). A correlation was found between high plasma AEP levels and a larger tumor size in GBM patients (r = 0.6, P = .03), which decreased dramatically after surgery.ConclusionsOur results indicate that AEP promotes GBM progression via inactivation of WT-p53 and may serve as a prognostic and therapeutic target for GBM.

| S-EPMC7156939 | biostudies-literature

Asparagine endopeptidase deficiency mitigates radiation-induced brain injury by suppressing microglia-mediated neuronal senescence

Project description:Mounting evidence supports the role of neuroinflammation in radiation-induced brain injury (RIBI), a chronic disease characterized by delayed and progressive neurological impairment. Asparagine endopeptidase (AEP), also known as legumain (LGMN), participates in multiple malignancies and neurodegenerative diseases and may potentially be involved in RIBI. Here, we found AEP expression was substantially elevated in the cortex and hippocampus of WT (Lgmn+/+) mice following whole-brain irradiation. Lgmn knockout (Lgmn-/-) alleviated neurological impairment caused by whole-brain irradiation by suppressing neuronal senescence. Bulk RNA and metabolomic sequencing revealed AEP’s involvement in the antigen processing and presentation pathway and neuroinflammation. This was further confirmed by co-culturing Lgmn+/+ primary neurons with the conditioned media derived from irradiated Lgmn+/+ or Lgmn-/- primary microglia. Furthermore, esomeprazole inhibited the enzymatic activity of AEP and RIBI. These findings identified AEP as a critical factor of neuroinflammation in RIBI, highlighting the prospect of targeting AEP as a therapeutic approach.

2024-05-01 | GSE246261 | GEO

Asparagine endopeptidase prompts breast cancer-related pericardial calcification by regulating IGF2 and integrin αvβ5

Project description:Cardiac calcification, commonly observed in age-related diseases, impairs heart function. However, its link to malignant tumors is poorly understood. Our study revealed that pericardial metallization occurs in up to 80% of breast cancer patients with pulmonary metastasis. We demonstrate a reciprocal relationship where breast cancer promotes pericardial calcification, which in turn accelerates cancer progression in both human patients and mice. Lung metastases increase macrophage and pre-osteoblast infiltration in the pericardial tissue, triggering inflammation and osteogenesis. Mechanistically, metastatic cancer cells in lungs highly express asparagine endopeptidase (AEP), which cleaves IGF2BP3 to enhance IGF2 level within these cells’ selves. These secreted AEP and IGF2 contribute to pericardial calcification by promoting osteoblast differentiation in heart tissue through activation of integrin αvβ5 and IGF1R respectively. Pharmacological inhibition of integrin αvβ5 and IGF1R effectively suppressed ectopic osteogenesis and disrupts the feedback loop from pericardial calcification to cancer progression. Taken together, these findings underscore the significance of managing pericardial calcification in breast cancer patients and offer potential treatment strategies.

2025-12-30 | GSE285907 | GEO

Multigenerational Proteolytic Inactivation of Restriction Upon Subtle Genomic Hypomethylation

Project description:Multigenerational Proteolytic Inactivation of Restriction Upon Subtle Genomic Hypomethylation

| PRJNA1179457 | ENA

Asparagine endopeptidase prompts breast cancer-related pericardial calcification by regulating IGF2 and integrin αvβ5

Project description:Asparagine endopeptidase prompts breast cancer-related pericardial calcification by regulating IGF2 and integrin αvβ5

| PRJNA1206968 | ENA

Asparagine endopeptidase deficiency mitigates radiation-induced brain injury by suppressing microglia-mediated neuronal senescence

Project description:Asparagine endopeptidase deficiency mitigates radiation-induced brain injury by suppressing microglia-mediated neuronal senescence

| PRJNA1032147 | ENA

Multigenerational Proteolytic Inactivation of Restriction Upon Subtle Genomic Hypomethylation in Pseudomonas aeruginosa

Project description:Multigenerational Proteolytic Inactivation of Restriction Upon Subtle Genomic Hypomethylation in Pseudomonas aeruginosa

| PRJNA1285262 | ENA

Neuroprotective actions of PIKE-L by inhibition of SET proteolytic degradation by asparagine endopeptidase.

Project description:Ischemia and seizure cause excessive neuronal excitation that is associated with brain acidosis and neuronal cell death. However, the molecular mechanism of acidification-triggered neuronal injury is incompletely understood. Here, we show that asparagine endopeptidase (AEP) is activated under acidic condition, cuts SET, an inhibitor of DNase, and triggers DNA damage in brain, which is inhibited by PIKE-L. SET, a substrate of caspases, was cleaved by acidic cytosolic extract independent of caspase activation. Fractionation of the acidic cellular extract yielded AEP that is required for SET cleavage. We found that kainate provoked AEP activation and SET cleavage at N175, triggering DNA nicking in wild-type, but not AEP null, mice. PIKE-L strongly bound SET and prevented its degradation by AEP, leading to resistance of neuronal cell death. Moreover, AEP also mediated stroke-provoked SET cleavage and cell death in brain. Thus, AEP might be one of the proteinases activated by acidosis triggering neuronal injury during neuroexcitotoxicity or ischemia.

| S-EPMC2819101 | biostudies-literature

Expression profiling of Eµ-Myc-driven lymphomas using a reversible switchable p53 allele modeling early and late stage p53 inactivation.

Project description:For the most frequently inactivated tumor suppressor p53, genetic mouse models have demonstrated regression of p53-null tumors upon p53 reactivation. While this was shown in tumor models driven by p53 loss as the initiating lesion, many tumors initially develop in the presence of wild-type p53, acquire aberrations in the p53 pathway to bypass p53-mediated tumor suppression, and inactivate p53 itself only at later stages during metastatic progression or therapy. To explore the efficacy of p53 reactivation in this scenario, we used a reversibly switchable p53 (p53ERTAM) mouse allele to generate Eµ-Myc-driven lymphomas in the presence of active p53 and, after full lymphoma establishment, switched off p53 to model late-stage p53 inactivation.

2019-10-18 | E-MTAB-8015 | biostudies-arrayexpress

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