Journal: Cell Death & Differentiation

Abbreviation

Cell Death Differ

Publisher

Nature

Journal Volumes

ISSN

1350-9047
1476-5403

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Publications 1 - 10 of 21
  • Mechanism of TAp73 inhibition by ΔNp63 and structural basis of p63/p73 hetero-tetramerization
    Item type: Journal Article
    Gebel, Jakob; Luh, Laura M.; Coutandin, Daniel; et al. (2016)
    Cell Death & Differentiation
  • Proteasome inhibition and oxidative reactions disrupt cellular homeostasis during heme stress
    Item type: Journal Article
    Vallelian, F.; Deuel, J. W.; Opitz, L.; et al. (2015)
    Cell Death & Differentiation
    Dual control of cellular heme levels by extracellular scavenger proteins and degradation by heme oxygenases is essential in diseases associated with increased heme release. During severe hemolysis or rhabdomyolysis, uncontrolled heme exposure can cause acute kidney injury and endothelial cell damage. The toxicity of heme was primarily attributed to its pro-oxidant effects; however additional mechanisms of heme toxicity have not been studied systematically. In addition to redox reactivity, heme may adversely alter cellular functions by binding to essential proteins and impairing their function. We studied inducible heme oxygenase (Hmox1)-deficient mouse embryo fibroblast cell lines as a model to systematically explore adaptive and disruptive responses that were triggered by intracellular heme levels exceeding the homeostatic range. We extensively characterized the proteome phenotype of the cellular heme stress responses by quantitative mass spectrometry of stable isotope-labeled cells that covered more than 2000 individual proteins. The most significant signals specific to heme toxicity were consistent with oxidative stress and impaired protein degradation by the proteasome. This ultimately led to an activation of the response to unfolded proteins. These observations were explained mechanistically by demonstrating binding of heme to the proteasome that was linked to impaired proteasome function. Oxidative heme reactions and proteasome inhibition could be differentiated as synergistic activities of the porphyrin. Based on the present data a novel model of cellular heme toxicity is proposed, whereby proteasome inhibition by heme sustains a cycle of oxidative stress, protein modification, accumulation of damaged proteins and cell death.
  • The SPRY domain of Pyrin, mutated in familial Mediterranean fever patients, interacts with inflammasome components and inhibits proIL-1β processing
    Item type: Journal Article
    Papin, S.; Cuenin, S.; Agostini, L.; et al. (2007)
    Cell Death & Differentiation
  • MINA-1 and WAGO-4 are part of regulatory network coordinating germ cell death and RNAi in C. elegans
    Item type: Journal Article
    Sendoel, Ataman; Subasic, Deni; Ducoli, Luca; et al. (2019)
    Cell Death & Differentiation
  • Mechanisms of haptoglobin protection against hemoglobin peroxidation triggered endothelial damage
    Item type: Journal Article
    Schaer, Christian A.; Deuel, Jeremy W.; Bittermann, Anne G.; et al. (2013)
    Cell Death & Differentiation
  • Correction to: Nrf3 promotes UV-induced keratinocyte apoptosis through suppression of cell adhesion
    Item type: Other Journal Item
    Siegenthaler, Beat; Defila, Claudia; Muzumdar, Sukalp; et al. (2020)
    Cell Death & Differentiation
  • Block one, unleash a hundred. Mechanisms of DAB2IP inactivation in cancer
    Item type: Journal Article
    Bellazzo, Arianna; Di Minin, Giulio; Collavin, Licio (2017)
    Cell Death & Differentiation
  • Targeting PML in triple negative breast cancer elicits growth suppression and senescence
    Item type: Journal Article
    Arreal, Leire; Piva, Marco; Fernández, Sonia; et al. (2020)
    Cell Death & Differentiation
    Oncogene addiction postulates that the survival and growth of certain tumor cells is dependent upon the activity of one oncogene, despite their multiple genetic and epigenetic abnormalities. This phenomenon provides a foundation for molecular targeted therapy and a rationale for oncogene-based stratification. We have previously reported that the Promyelocytic Leukemia protein (PML) is upregulated in triple negative breast cancer (TNBC) and it regulates cancer-initiating cell function, thus suggesting that this protein can be therapeutically targeted in combination with PML-based stratification. However, the effects of PML perturbation on the bulk of tumor cells remained poorly understood. Here we demonstrate that TNBC cells are addicted to the expression of this nuclear protein. PML inhibition led to a remarkable growth arrest combined with features of senescence in vitro and in vivo. Mechanistically, the growth arrest and senescence were associated to a decrease in MYC and PIM1 kinase levels, with the subsequent accumulation of CDKN1B (p27), a trigger of senescence. In line with this notion, we found that PML is associated to the promoter regions of MYC and PIM1, consistent with their direct correlation in breast cancer specimens. Altogether, our results provide a feasible explanation for the functional similarities of MYC, PIM1, and PML in TNBC and encourage further study of PML targeting strategies for the treatment of this breast cancer subtype.
  • Cell type-specific Nogo-A gene ablation promotes axonal regeneration in the injured adult optic nerve
    Item type: Journal Article
    Vajda, F.; Jordi, N.; Dalkara, D.; et al. (2015)
    Cell Death & Differentiation
  • The scramblases VMP1 and TMEM41B are required for primitive endoderm specification by targeting WNT signaling
    Item type: Journal Article
    Holzner, Markus; Sonicki, Tea; Hunn, Hugo; et al. (2025)
    Cell Death & Differentiation
    The ER-resident proteins VMP1 and TMEM41B share a conserved DedA domain, which confers lipid scramblase activity. Loss of either gene results in embryonic lethality in mice and defects in autophagy and lipid droplet metabolism. To investigate their role in pluripotency and lineage specification, we generated Vmp1 and Tmem41b mutations in mouse embryonic stem cells (ESCs). We observed that ESCs carrying mutations in Vmp1 and Tmem41b show robust self-renewal and an unperturbed pluripotent expression profile but accumulate LC3-positive autophagosomes and lipid droplets consistent with defects in autophagy and lipid metabolism. ESCs carrying combined mutations in Vmp1 and Tmem41b can differentiate into a wide range of embryonic cell types. However, differentiation into primitive endoderm-like cells in culture is impaired, and the establishment of extra-embryonic endoderm stem (XEN) cells is delayed. Mechanistically, we show the deregulation of genes that are associated with WNT signaling. This is further confirmed by cell surface proteome profiling, which identified a significant reduction of the WNT-receptor FZD2 at the plasma membrane in Vmp1 and Tmem41b double mutant ESCs. Importantly, we show that transgenic expression of Fzd2 rescues XEN differentiation. Our findings identify the role of the lipid scramblases VMP1 and TMEM41B in WNT signaling during extra-embryonic endoderm development and characterize their distinct and overlapping functions.
Publications 1 - 10 of 21