Biology subjects

Reiff, T.

Publications and source records attributed to Reiff, T..

5 recordsLinked to original sources

bioRxiv2024

The EIF4EBP1 gene encoding 4EBP1 is transcriptionally upregulated by MYC and linked to shorter survival in medulloblastoma

Medulloblastoma (MB) is the most common malignant brain tumor in childhood and is stratified into four molecular groups - WNT, SHH, Group 3 and Group 4. Group 3 MB patients exhibit the poorest prognosis, with a 5-year overall survival of <60%, followed by Group 4 MB patients. Apart from MYC amplification in a subset of Group 3 MBs, the molecular pathomechanisms driving aggressiveness of these tumors remain incompletely characterized. The gene encoding the mTOR substrate and mRNA translation inhibitor eukaryotic translation initiation factor 4E-binding protein 1 (EIF4EBP1) represents a possible MYC target gene whose corresponding protein, 4EBP1, was shown to be more active in Group 3 versus Group 4 MBs. However, the prognostic role of 4EBP1 in MB and the mechanisms supporting 4EBP1 overexpression in Group 3 MB are still elusive. We analyzed EIF4EBP1 mRNA expression in publicly available data sets and found an upregulation in MB as compared to non-neoblastic brain. EIF4EBP1 mRNA expression levels were higher in Group 3 compared to Group 4 MBs. EIF4EBP1 mRNA expression was correlated with MYC expression, most prominently in Group 3 MBs. Survival analyses highlighted that high EIF4EBP1 mRNA expression was associated with reduced overall and event-free survival across all MB patients and in Group 3/Group 4 MB patients. Immunohistochemical evaluation of 4EBP1 protein expression in MB tissues confirmed that high levels of 4EBP1 are associated with poor outcome. Functional analyses revealed that MYC directly regulates EIF4EBP1 promoter activity, providing a mechanism for increased EIF4EBP1 mRNA levels in Group 3 MBs. Finally, we observed that 4EBP1 may support colony formation of in vitro cultured MB cells. Our data highlight that transcriptional upregulation of EIF4EBP1 by MYC promotes in vitro tumorigenicity of MB cells and associates with shorter survival of MB patients.

cancer biology↗

bioRxiv2024

Oncogenic RAS signaling suppresses ferroptosis via transcriptional upregulation of GCH1

Ferroptosis is an iron-dependent form of regulated cell death arising from excessive lipid peroxidation. The role of oncogenic RAS signaling in modulating the cellular response to ferroptosis is controversial. While seminal studies described that oncogenic RAS transformation drives a synthetic lethal vulnerability to archetypal ferroptosis inducers including erastin (eradicator of RAS and ST-expressing cells) and RSL3 (Ras selective lethal 3), more recent work suggest that oncogenic RAS signaling may confer ferroptosis resistance. Thus, the impact of oncogenic RAS expression on ferroptosis sensitivity is still poorly understood. Here, using orthogonal cellular systems across multiple classes of ferroptosis- inducing agents, as well as in silico therapeutic drug-response analyses, we provide unifying evidence that oncogenic RAS signaling suppresses ferroptosis. Integrated proteo- and transcriptomic analyses in oncogenic RAS-transformed cells further uncovered that RAS signaling upregulates the ferroptosis suppressor GTP cyclohydrolase I (GCH1) via transcriptional induction by the transcription factor ETS1 downstream of the RAS-MAPK signaling cascade. Targeted repression of Gch1 or of Gch1-controlled tetrahydrobiopterin (BH4) synthesis pathway is sufficient to sensitize RAS-mutant cell lines to ferroptosis in 2D and 3D cell models, as well as in tumor organoids and tumor xenografts, highlighting a mechanism through which RAS promotes resistance to ferroptosis induction. Furthermore, we found that GCH1 expression is clinically relevant and correlates with RAS signaling activation in human cancers. Overall, this study redefines oncogenic RAS signaling to be a ferroptosis suppressor, and identifies GCH1 as a mediator of this effect and a potential clinical target for the sensitization of RAS-driven cancers to ferroptosis-inducing agents. Significance StatementAlthough it is commonly accepted that ferroptosis induction is a mutant RAS-selective lethality, accumulating evidence suggests that oncogenic RAS protects cells against this form of cell death. However, a systematic survey establishing the relationship between RAS and ferroptosis sensitivity is lacking, and the molecular mechanisms this entails are still poorly understood. Here, we report across RAS-mutant isoforms, in diverse cellular models, and using multiple ferroptosis-inducing compounds that oncogenic RAS consistently suppresses ferroptosis. Further, we show that oncogenic RAS-mediated ferroptosis suppression is attributed to the upregulation of GCH1 and its downstream metabolite, tetrahydrobiopterin. Our study delivers a shift towards a new paradigm in which oncogenic RAS confers ferroptosis resistance, and a potential clinical strategy to re-engage ferroptosis sensitivity in RAS-driven cancers.

cancer biology↗

bioRxiv2022

The septate junction component Bark beetle is required for Drosophila intestinal barrier function and homeostasis

Age-related loss of intestinal barrier function has been found across species, and the causes remain unknown. The intestinal epithelial barrier is maintained by tight junctions (TJs) in mammals and septate junctions (SJs) in insects. Specialized tricellular junctions (TCJs) are found at the nexus of three adjacent cell membranes, and we showed previously that aging results in mis-localization of the tricellular SJ (tSJ) component Gliotactin (Gli) in enterocytes (ECs) of the Drosophila melanogaster intestine. In embryonic epithelia, the tSJ protein Bark beetle (Bark) recruits Gli to tSJs, which prompted us to investigate Bark function in the intestine. Bark protein localization decreases at tSJs in aged flies. EC-specific bark depletion in young flies led to hallmarks of intestinal aging and shortened lifespan, whereas depletion of bark in progenitor cells reduced Notch activity, biasing differentiation toward the secretory lineage. Together, our data implicate Bark in EC maturation, maintenance of intestinal barrier integrity, and homeostasis. Understanding the assembly and maintenance of tSJs to ensure barrier integrity may lead to strategies to improve tissue integrity when function is compromised.

cell biology↗

bioRxiv2020

Ecdysone steroid hormone remote controls intestinal stem cell fate decisions via the PPARγ-homologue E75B in Drosophila

Developmental studies revealed fundamental principles on how organ size and function is achieved, but less is known about organ adaptation to new physiological demands. In fruit flies, juvenile hormone (JH) induces intestinal stem cell (ISC) driven absorptive epithelial expansion balancing energy uptake with increased energy demands of pregnancy. Here, we show 20-Hydroxy-Ecdysone (20HE)-signaling controlling organ homeostasis with physiological and pathological implications. Upon mating, 20HE titer in ovaries and hemolymph are increased and act on nearby midgut progenitors inducing Ecdysone-induced-protein-75B (Eip75B). Strikingly, the PPAR{gamma}-homologue Eip75B drives ISC daughter cells towards absorptive enterocyte lineage ensuring epithelial growth. To our knowledge, this is the first time a systemic hormone is shown to direct local stem cell fate decisions. Given the protective, but mechanistically unclear role of steroid hormones in female colorectal cancer patients, our findings suggest a tumor-suppressive role for steroidal signaling by promoting postmitotic fate when local signaling is deteriorated.

developmental biology↗

bioRxiv2018

The Notch and EGFR signaling regulate caspase inhibitor Diap1 to match supply with intestinal demand

The regenerative activity of adult stem cells carries a high risk of cancer, particularly in highly renewable tissues. To guarantee that the correct organ size is attained and to cope with the continual risk of cancer, developing tissues often use programmed cell death (PCD) as an adaptive mechanism to cull excess and abnormal cells. Members of the family of Inhibitor of Apoptosis Proteins (IAPs) inhibit caspases and cell death and are often overexpressed in cancer. Here, we show that Diap1 is expressed in committed progenitor (enteroblast) cells in the adult Drosophila intestine. Blocking endogenous caspases uncovered that more than half of enteroblasts produced by intestinal stem cells (ISCs) are actively eliminated by apoptosis in the physiological intestine and also led to tumorigenesis. We find that antagonistic interplay between the Notch and EGFR signaling on Diap1 regulation governs the enteroblast cell death or survival decision via the conserved Klumpfuss/WT1-Lozenge/RUNX axis, which also regulates of differentiation plasticity of enteroblasts. These data provide new insights into how apoptosis drives adult tissue renewal and protection against tumors.

cell biology↗