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1.
EMBO J ; 37(5)2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29363506

RESUMO

The atypical E2Fs, E2F7 and E2F8, act as potent transcriptional repressors of DNA replication genes providing them with the ability to induce a permanent S-phase arrest and suppress tumorigenesis. Surprisingly in human cancer, transcript levels of atypical E2Fs are frequently elevated in proliferating cancer cells, suggesting that the tumor suppressor functions of atypical E2Fs might be inhibited through unknown post-translational mechanisms. Here, we show that atypical E2Fs can be directly phosphorylated by checkpoint kinase 1 (Chk1) to prevent a permanent cell cycle arrest. We found that 14-3-3 protein isoforms interact with both E2Fs in a Chk1-dependent manner. Strikingly, Chk1 phosphorylation and 14-3-3-binding did not relocate or degrade atypical E2Fs, but instead, 14-3-3 is recruited to E2F7/8 target gene promoters to possibly interfere with transcription. We observed that high levels of 14-3-3 strongly correlate with upregulated transcription of atypical E2F target genes in human cancer. Thus, we reveal that Chk1 and 14-3-3 proteins cooperate to inactivate the transcriptional repressor functions of atypical E2Fs. This mechanism might be of particular importance to cancer cells, since they are exposed frequently to DNA-damaging therapeutic reagents.


Assuntos
Proteínas 14-3-3/metabolismo , Pontos de Checagem do Ciclo Celular/fisiologia , Quinase 1 do Ponto de Checagem/metabolismo , Fator de Transcrição E2F7/antagonistas & inibidores , Neoplasias/patologia , Proteínas Repressoras/antagonistas & inibidores , Apoptose/fisiologia , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Replicação do DNA/genética , Fator de Transcrição E2F7/metabolismo , Células HEK293 , Células HeLa , Humanos , Fosforilação , Regiões Promotoras Genéticas/genética , Ligação Proteica , Biossíntese de Proteínas/genética , Proteínas Repressoras/metabolismo
2.
Mol Syst Biol ; 14(6): e8227, 2018 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-29945941

RESUMO

Intestinal organoids accurately recapitulate epithelial homeostasis in vivo, thereby representing a powerful in vitro system to investigate lineage specification and cellular differentiation. Here, we applied a multi-omics framework on stem cell-enriched and stem cell-depleted mouse intestinal organoids to obtain a holistic view of the molecular mechanisms that drive differential gene expression during adult intestinal stem cell differentiation. Our data revealed a global rewiring of the transcriptome and proteome between intestinal stem cells and enterocytes, with the majority of dynamic protein expression being transcription-driven. Integrating absolute mRNA and protein copy numbers revealed post-transcriptional regulation of gene expression. Probing the epigenetic landscape identified a large number of cell-type-specific regulatory elements, which revealed Hnf4g as a major driver of enterocyte differentiation. In summary, by applying an integrative systems biology approach, we uncovered multiple layers of gene expression regulation, which contribute to lineage specification and plasticity of the mouse small intestinal epithelium.


Assuntos
Biologia Computacional , Intestinos/citologia , Organogênese , Organoides/citologia , Animais , Regulação da Expressão Gênica , Camundongos , Organogênese/genética , Células-Tronco
3.
EMBO Mol Med ; 15(4): e15674, 2023 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-36855912

RESUMO

Besides genetic alterations, the cellular environment also determines disease onset and progression. When different cell types contribute to disease outcome, this imposes environmental challenges as different cell types likely differ in their extracellular dependencies. Hsa-microRNA-31-5p (miR-31) is highly expressed in keratinocytes of psoriatic skin, and we show that expression in keratinocytes is induced by limited glucose availability and enables increased survival under limiting glucose conditions by increasing glutamine metabolism. In addition, miR-31 expression results in not only secretion of specific metabolites (aspartate and glutamate) but also secretion of immunomodulatory factors. We show that this miR-31-induced secretory phenotype is sufficient to induce Th17 cell differentiation, a hallmark of psoriasis. Inhibitors of miR31-induced metabolic rewiring and metabolic crosstalk with immune cells alleviate psoriasis pathology in a mouse model of psoriasis. Together our data illustrate an emerging concept of metabolic interaction across cell compartments that characterizes disease development, which can be employed to design effective treatment options for disease, as shown here for psoriasis.


Assuntos
MicroRNAs , Psoríase , Animais , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Queratinócitos , Psoríase/genética , Pele/patologia , Diferenciação Celular , Proliferação de Células/genética
4.
Clin Transl Immunology ; 9(10): e1186, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33033617

RESUMO

The gasdermins, family of pore-forming proteins, are emerging key regulators of infection, autoinflammation and antitumor immunity. Multiple studies have recently characterised their crucial roles in driving pyroptosis, a lytic pro-inflammatory type of cell death. Additionally, gasdermins also act as key effectors of NETosis, secondary necrosis and apoptosis. In this review, we will address current understanding of the mechanisms of gasdermin activation and further describe the protective and detrimental roles of gasdermins in host defence and autoinflammatory diseases. These data suggest that gasdermins play a prominent role in innate immunity and autoinflammatory disorders, thereby providing potential new therapeutic avenues for the treatment of infection and autoimmune disease.

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