Nucleoptosis: Nucleolar ISG20L2 mediates cell death through genomic DNA degradation
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE256151 | GEO | 2025/05/01
REPOSITORIES: GEO
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Project description:Nucleoptosis: Nucleolar ISG20L2 mediates cell death through genomic DNA degradation
| PRJNA1078328 | ENA
Project description:Autophagy is a catabolic membrane trafficking process involved in degradation of cellular constituents through lysosomes, which maintains cell and tissue homeostasis. While much attention has been focused on autophagic turnover of cytoplasmic materials, little is known regarding the role of autophagy in degrading nuclear components. Here we report that autophagy machinery mediates degradation of nuclear lamina in mammalian cells, a process we term laminophagy. The autophagy protein LC3 is present in the nucleus and directly interacts with the nuclear lamina protein Lamin B1, and associates with lamin-associated domains (LADs) on chromatin. This interaction does not downregulate Lamin B1 during starvation, but mediates nuclear lamina degradation upon tumorigenic insults, such as by oncogenic Ras. Laminophagy is achieved by nucleus-to-cytosol transport that delivers Lamin B1 to lysosome for degradation. Inhibiting autophagy or LC3-Lamin B1 interaction prevents oncogenic Ras-induced Lamin B1 loss and delays oncogene-induced cell cycle arrest. Our study unveils a role of autophagy in degrading nuclear materials, and suggests laminophagy as a guarding mechanism protecting cells from tumorigenesis.
2015-10-08 | GSE63440 | GEO
Project description:Tamoxifen is widely used to treat estrogen receptor-positive breast cancer. Recent findings that tamoxifen and its derivative 4-hydroxytamoxifen (OHT) can exert estrogen receptor-independent cytotoxic effects have prompted the initiation of clinical trials to evaluate its use in estrogen receptor-negative malignancies. For example, tamoxifen and OHT exert cytotoxic effects in malignant peripheral nerve sheath tumors (MPNST) where estrogen is not involved. In this study, we gained insights into the estrogen receptor-independent cytotoxic effects of OHT by studying how it kills MPNST cells. Although caspases were activated following OHT treatment, caspase inhibition provided no protection from OHT-induced death. Rather, OHT-induced death in MPNST cells was associated with autophagic induction and attenuated by genetic inhibition of autophagic vacuole formation. Mechanistic investigations revealed that OHT stimulated autophagic degradation of K-Ras, which is critical for survival of MPNST cells. Similarly, we found that OHT induced K-Ras degradation in breast, colon, glioma, and pancreatic cancer cells. Our findings describe a novel mechanism of autophagic death triggered by OHT in tumor cells that may be more broadly useful clinically in cancer treatment.
| S-EPMC3715566 | biostudies-literature
Project description:β-Catenin is constantly degraded through the ubiquitin-proteasomal pathway. In this study, we report that a different type of β-catenin degradation is causally involved in epidermal cell death. We observed that reactive oxygen species (ROS) caused β-catenin degradation in the epidermal cells through a caspase-dependent mechanism, which results in disruption of cell adhesion. Disruption of cell adhesion increased ROS and activated caspases. Upregulation of the intact β-catenin blocked ROS accumulation and caspase activation. These results indicate that a feed-forward loop consisting of ROS, caspases activation and β-catenin degradation induces epidermal cell death.
| S-EPMC3131442 | biostudies-literature
Project description:Cell death occurs in all eukaryotes, but it is still not known whether some core steps of the cell death process are conserved. We investigated this using the protist Dictyostelium. The dissection of events in Dictyostelium vacuolar developmental cell death was facilitated by the sequential requirement for two distinct exogenous signals. An initial exogenous signal (starvation and cAMP) recruited some cells into clumps. Only within these clumps did subsequent cell death events take place. Contrary to our expectations, already this initial signal provoked nucleolar disorganization and irreversible inhibition of rRNA and DNA synthesis, reflecting marked cell dysfunction. The initial signal also primed clumped cells to respond to a second exogenous signal (differentiation-inducing factor-1 or c-di-GMP), which led to vacuolization and synthesis of cellulose encasings. Thus, the latter prominent hallmarks of developmental cell death were induced separately from initial cell dysfunction. We propose that (1) in Dictyostelium vacuolization and cellulose encasings are late, organism-specific, hallmarks, and (2) on the basis of our observations in this protist and of similar previous observations in some cases of mammalian cell death, early inhibition of rRNA synthesis and nucleolar disorganization may be conserved in some eukaryotes to usher in developmental cell death.
| S-EPMC5386361 | biostudies-literature
Project description:Acetaminophen (APAP) is one of the most frequently used drugs; however, its overdose leads to acute liver injury. Recently, studies have reported that the adduction of peroxiredoxin 6 (PRDX6), a member of the PRDX family of antioxidant enzymes, is associated with liver diseases. However, the role of PRDX6 in APAP-induced liver injury remains unclear. Here, we assessed both age-matched (about 12 weeks) PRDX6-overexpressing transgenic mice (PRDX6 mice) and wild type (WT) mice presenting acute liver injury induced by the intraperitoneal injection of APAP (500 mg/kg). Although PRDX6 is known as an antioxidant enzyme, PRDX6 mice unexpectedly demonstrated severe liver injury following APAP injection compared with WT mice. We observed that PRDX6 was hyperoxidized after APAP administration. Additionally, calcium-independent phospholipase A2 (iPLA2) activity and lysophosphatidylcholine (LPC) levels were markedly elevated in PRDX6 mice following APAP administration. Moreover, APAP-induced JNK phosphorylation was considerably increased in the liver of PRDX6 mice. MJ33, an inhibitor of PRDX6, attenuated APAP-induced liver injury both in WT and PRDX6 mice. Notably, MJ33 reduced the APAP-induced increase in JNK activation, iPLA2 activity, and LPC levels. Although SP600125, a JNK inhibitor, abolished APAP-induced liver injury, it failed to affect the APAP-induced hyperoxidation of PRDX6, iPLA2 activity, and LPC levels. These results suggested that PRDX6 was converted to the hyperoxidized form by the APAP-induced high concentration of hydrogen peroxides. In the liver, hyperoxidized PRDX6 induced cellular toxicity via JNK activation by enhancing iPLA2 activity and LPC levels; this mechanism appears to be a one-way cascade.
| S-EPMC7068129 | biostudies-literature
Project description:Bnip3 is a pro-apoptotic member of the Bcl-2 family that is down-regulated in pancreatic cancers, which correlates with resistance to chemotherapy and a worsened prognosis. In contrast, Bnip3 is up-regulated in heart failure and contributes to loss of myocardial cells during I/R (ischaemia/reperfusion). Bnip3 exerts its action at the mitochondria, but the mechanism by which Bnip3 mediates mitochondrial dysfunction is not clear. In the present study, we have identified Bax and Bak as downstream effectors of Bnip3-mediated mitochondrial dysfunction. Bnip3 plays a role in hypoxia-mediated cell death, but MEFs (mouse embryonic fibroblasts) derived from mice deficient in Bax and Bak were completely resistant to hypoxia even with substantial up-regulation of Bnip3. These cells were also resistant to Bnip3 overexpression, but re-expression of Bax or Bak restored susceptibility to Bnip3, suggesting that Bnip3 can act via either Bax or Bak. In contrast, Bnip3 overexpression in wild-type MEFs induced mitochondrial dysfunction with loss of membrane potential and release of cytochrome c. Cell death by Bnip3 was reduced in the presence of mPTP (mitochondrial permeability transition pore) inhibitors, but did not prevent Bnip3-mediated activation of Bax or Bak. Moreover, overexpression of Bnip3DeltaTM, a dominant-negative form of Bnip3, reduced translocation of GFP (green fluorescent protein)-Bax to mitochondria during sI/R (simulated I/R) in HL-1 myocytes. Similarly, down-regulation of Bnip3 using RNA interference decreased activation of Bax in response to sI/R in HL-1 myocytes. These results suggest that Bnip3 mediates mitochondrial dysfunction through activation of Bax or Bak which is independent of mPTP opening.
| S-EPMC2267317 | biostudies-other
Project description:The nuclear architecture of mammalian cells can be altered as a consequence of anomalous accumulation of nuclear proteins or genomic alterations. Most of the knowledge about nuclear dynamics comes from studies on cancerous cells. How normal healthy cells maintain genome stability, avoiding accumulation of nuclear damaged material, is less understood. Here, we describe that primary mouse embryonic fibroblasts develop a basal level of nuclear buds and micronuclei, which increase after etoposide-induced DNA double-stranded breaks. Both basal and induced nuclear buds and micronuclei colocalize with the autophagic proteins BECN1 and LC3B (also known as MAP1LC3B) and with acidic vesicles, suggesting their clearance by nucleophagy. Some of the nuclear alterations also contain autophagic proteins and type II DNA topoisomerases (TOP2A and TOP2B), or the nucleolar protein fibrillarin, implying they are also targets of nucleophagy. We propose that basal nucleophagy contributes to genome and nuclear stability, as well as in response to DNA damage.
| S-EPMC10112964 | biostudies-literature
Project description:The histone methyltransferase DOT1L catalyzes methylation of H3K79 and it is highly conserved in mammals. DOT1L plays a functional role in several biological processes including cell cycle regulation, DNA repair, RNA splicing and gene expression, suggesting a complex role in chromatin organization and regulation. Such a remarkable range of functions performed by DOT1l can be the result, at least partially, of its interaction with different proteins and presence in different complexes. Here, we characterized the interaction of DOT1L with the nucleolar protein NPM1 and the impact of the DOT1L/NPM1 complex on nucleoli organization and activity. We show that i) DOT1L interacts preferentially with monomeric NPM1 in the nucleus; ii) DOT1L interaction with NPM1 is key to maintain their protein homeostasis; iii) NPM1 depletion results in H3K79me2 upregulation at chromatin remodeling genes; iv) DOT1L/NPM1 complex preserved peri-nucleolar heterochromatin organization via epigenetic mechanisms. Our findings unravel the molecular mechanisms employed by the DOT1L/NPM1 complex to maintain heterochromatin organization around the nucleoli and shed light on one aspect of the complex role of DOT1L in chromatin dynamics.
2024-01-01 | GSE223361 | GEO
Project description:Leelamine is a promising compound for the treatment of cancer; however, the molecular mechanisms leading to leelamine-mediated cell death have not been identified. This report shows that leelamine is a weakly basic amine with lysosomotropic properties, leading to its accumulation inside acidic organelles such as lysosomes. This accumulation leads to homeostatic imbalance in the lysosomal endosomal cell compartments that disrupts autophagic flux and intracellular cholesterol trafficking as well as receptor-mediated endocytosis. Electron micrographs of leelamine-treated cancer cells displayed accumulation of autophagosomes, membrane whorls, and lipofuscin-like structures, indicating disruption of lysosomal cell compartments. Early in the process, leelamine-mediated killing was a caspase-independent event triggered by cholesterol accumulation, as depletion of cholesterol using β-cyclodextrin treatment attenuated the cell death and restored the subcellular structures identified by electron microscopy. Protein microarray-based analyses of the intracellular signaling cascades showed alterations in RTK-AKT/STAT/MAPK signaling cascades, which was subsequently confirmed by Western blotting. Inhibition of Akt, Erk, and Stat signaling, together with abnormal deregulation of receptor tyrosine kinases, was caused by the inhibition of receptor-mediated endocytosis. This study is the first report demonstrating that leelamine is a lysosomotropic, intracellular cholesterol transport inhibitor with potential chemotherapeutic properties leading to inhibition of autophagic flux and induction of cholesterol accumulation in lysosomal/endosomal cell compartments. Importantly, the findings of this study show the potential of leelamine to disrupt cholesterol homeostasis for treatment of advanced-stage cancers.
| S-EPMC4373557 | biostudies-literature