Cell competition in development, homeostasis and cancer

Nature Reviews Molecular Cell Biology, Год журнала: 2022, Номер 24(3), С. 221 - 236

Опубликована: Сен. 29, 2022

Язык: Английский

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The integrated stress response in metabolic adaptation

Journal of Biological Chemistry, Год журнала: 2024, Номер 300(4), С. 107151 - 107151

Опубликована: Март 9, 2024

The Integrated Stress Response (ISR) refers to signaling pathways initiated by stress-activated eIF2‹ kinases. Distinct kinases respond different stress signals, including amino acid deprivation and mitochondrial stress. Such stress-induced phosphorylation attenuates general mRNA translation and, at the same time, stimulates preferential of specific downstream factors orchestrate an adaptive gene expression program. In recent years, there have been significant new advances in our understanding ISR during metabolic adaptation. Here, I discuss those advances, reviewing among others activation mechanisms response addition, review how regulates changes impact physiology pathology various disease models.

Язык: Английский

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The homeostatic regulation of ribosome biogenesis

Seminars in Cell and Developmental Biology, Год журнала: 2022, Номер 136, С. 13 - 26

Опубликована: Апрель 16, 2022

Язык: Английский

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Cell competition: emerging signaling and unsolved questions

FEBS Letters, Год журнала: 2024, Номер 598(4), С. 379 - 389

Опубликована: Фев. 1, 2024

Multicellular communities have an intrinsic mechanism that optimizes their structure and function via cell–cell communication. One of the driving forces for such self‐organization multicellular system is cell competition, elimination viable unfit or deleterious cells interaction. Studies in Drosophila mammals identified multiple mechanisms competition caused by different types mutations cellular changes. Intriguingly, recent studies found “losers” commonly show reduced protein synthesis. In , reduction synthesis levels loser phosphorylation translation initiation factor eIF2α a bZip transcription Xrp1. Given variety stresses converge on thus global inhibition synthesis, may be machinery fitness removing stressed cells. this review, we summarize discuss emerging signaling critical unsolved questions, as well role competition.

Язык: Английский

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The transcription factor Xrp1 orchestrates both reduced translation and cell competition upon defective ribosome assembly or function

eLife, Год журнала: 2022, Номер 11

Опубликована: Фев. 18, 2022

Ribosomal Protein ( Rp ) gene haploinsufficiency affects translation rate, can lead to protein aggregation, and causes cell elimination by competition with wild type cells in mosaic tissues. We find that the modest changes ribosomal subunit levels observed were insufficient for these effects, which all depended on AT-hook, bZip domain Xrp1. Xrp1 reduced global through PERK-dependent phosphorylation of eIF2α. eIF2α was itself sufficient enable otherwise cells, but expression, not as downstream effector Unexpectedly, many other defects reducing ribosome biogenesis or function (depletion TAF1B, eIF2, eIF4G, eIF6, eEF2, eEF1α1, eIF5A), also increased enabled competition. This expression induced depletions. In absence Xrp1, differences between themselves trigger is shown here be a sequence-specific transcription factor regulates transposable elements well single-copy genes. Thus, master regulator triggers multiple consequences stresses key instigator

Язык: Английский

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Cell competition is driven by Xrp1-mediated phosphorylation of eukaryotic initiation factor 2α

PLoS Genetics, Год журнала: 2021, Номер 17(12), С. e1009958 - e1009958

Опубликована: Дек. 6, 2021

Cell competition is a context-dependent cell elimination via cell-cell interaction whereby unfit cells (‘losers’) are eliminated from the tissue when confronted with fitter (‘winners’). Despite extensive studies, mechanism that drives loser’s death and its physiological triggers remained elusive. Here, through genetic screen in Drosophila , we find endoplasmic reticulum (ER) stress causes competition. Mechanistically, ER upregulates bZIP transcription factor Xrp1, which promotes phosphorylation of eukaryotic translation initiation eIF2α kinase PERK, leading to elimination. Surprisingly, our data show different such as ribosomal protein mutations or RNA helicase Hel25E converge on upregulation leads thus reduction global synthesis apoptosis wild-type cells. These findings not only uncover core pathway but also open way understanding

Язык: Английский

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Upregulation of ribosome biogenesis via canonical E-boxes is required for Myc-driven proliferation

Developmental Cell, Год журнала: 2022, Номер 57(8), С. 1024 - 1036.e5

Опубликована: Апрель 1, 2022

The transcription factor Myc drives cell growth across animal phyla and is activated in most forms of human cancer. However, it unclear which target genes need to be regulated induce whether multiple targets act additively or if induction each individually necessary. Here, we identified whose regulation conserved between humans flies deleted Myc-binding sites (E-boxes) the promoters fourteen these Drosophila. E-box mutants essential were homozygous viable, indicating that E-boxes are not required for basal expression. Eight mutations led Myc-like phenotypes; strongest mutant, ppanEbox-/-, also made resistant Myc-induced without affecting apoptosis. ppanEbox-/- healthy display only a minor developmental delay, suggesting may possible treat prevent tumorigenesis by targeting individual downstream Myc.

Язык: Английский

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Ribosomal protein mutations and cell competition: autonomous and nonautonomous effects on a stress response

Genetics, Год журнала: 2023, Номер 224(3)

Опубликована: Июнь 2, 2023

Abstract Ribosomal proteins (Rps) are essential for viability. Genetic mutations affecting Rp genes were first discovered in Drosophila, where they represent a major class of haploinsufficient mutations. One mutant copy gives rise to the dominant “Minute” phenotype, characterized by slow growth and small, thin bristles. Wild-type (WT) Minute cells compete mosaics, that is, Rp+/− preferentially lost when their neighbors wild-type genotype. Many features gene haploinsufficiency (i.e. phenotypes) mediated transcriptional program. In reduced translation under control Xrp1, bZip-domain transcription factor induced leads ultimately phosphorylation eIF2α consequently inhibition most translation. phenotypes also transcriptionally yeast mammals. mammals, Impaired Ribosome Biogenesis Checkpoint activates p53. Recent findings link other cellular stresses, including DNA damage response endoplasmic reticulum stress. We suggest cell competition results from nonautonomous inputs stress responses, bringing decisions between adaptive apoptotic outcomes influence nearby cells. eliminates aneuploid which loss chromosome haploinsufficiency. The effects on whole organism, flies or humans with Diamond-Blackfan Anemia, may be inevitable consequences pathways useful eliminating individual mosaics. Alternatively, apparently deleterious organism might adaptive, preventing even more detrimental outcomes. example, p53 activation appears suppress oncogenic

Язык: Английский

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Cell competition and the regulation of protein homeostasis

Current Opinion in Cell Biology, Год журнала: 2024, Номер 87, С. 102323 - 102323

Опубликована: Фев. 1, 2024

The process of embryonic development involves remarkable cellular plasticity, which governs the coordination between cells necessary to build an organism. One role this plasticity is ensure that when aberrant are eliminated, growth adjustment occurs so size tissue maintained. An important regulator ensures cooperation a fitness-sensing mechanism termed cell competition. During competition, with defects lower fitness but do not affect viability, such as those cause impaired signal transduction, slower growth, mitochondrial dysregulation or protein homeostasis, killed surrounded by fitter cells. This accompanied compensatory proliferation surviving underlying factors and mechanisms demarcate certain less fit than their neighbouring losers competition still relatively unknown. Recent evidence has pointed proteotoxic stress hallmarks these loser Here, we review recent advances in area, focussing on activity homeostasis major determining competitive during importance proteostasis fitness.

Язык: Английский

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Xrp1 governs the stress response program to spliceosome dysfunction

Nucleic Acids Research, Год журнала: 2024, Номер 52(5), С. 2093 - 2111

Опубликована: Фев. 2, 2024

Abstract Co-transcriptional processing of nascent pre-mRNAs by the spliceosome is vital to regulating gene expression and maintaining genome integrity. Here, we show that deficiency functional U5 small nuclear ribonucleoprotein particles (snRNPs) in Drosophila imaginal cells causes extensive transcriptome remodeling accumulation highly mutagenic R-loops, triggering a robust stress response cell cycle arrest. Despite compromised proliferative capacity, snRNP-deficient increased protein translation size, causing intra-organ growth disbalance before being gradually eliminated via apoptosis. We identify Xrp1-Irbp18 heterodimer as primary driver transcriptional cellular program downstream snRNP malfunction. Knockdown Xrp1 or Irbp18 attenuated JNK p53 activity, restored normal progression growth, inhibited death. Reducing Xrp1-Irbp18, however, did not rescue splicing defects, highlighting requirement accurate for tissue homeostasis. Our work provides novel insights into crosstalk between DNA damage defines critical sensor malfunction mediator stress-induced senescence program.

Язык: Английский

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