scholarly journals Translation reprogramming by eIF3 linked to glioblastoma resistance

NAR Cancer ◽  
2020 ◽  
Vol 2 (3) ◽  
Author(s):  
Juliette Bertorello ◽  
Julie Sesen ◽  
Julia Gilhodes ◽  
Solène Evrard ◽  
Monique Courtade-Saïdi ◽  
...  
Keyword(s):  
Translational Control ◽  
Protein Translation ◽  
Intrinsic Resistance ◽  
Cell Behaviors ◽  
Medical Need ◽  
Multimeric Complex ◽  
Initiation Of Translation ◽  
Cancer Initiation ◽  
Current Therapies ◽  
Underlying Mechanisms

Abstract Intrinsic resistance to current therapies, leading to dismal clinical outcomes, is a hallmark of glioblastoma multiforme (GBM), the most common and aggressive brain tumor. Understanding the underlying mechanisms of such malignancy is, therefore, an urgent medical need. Deregulation of the protein translation machinery has been shown to contribute to cancer initiation and progression, in part by driving selective translational control of specific mRNA transcripts involved in distinct cancer cell behaviors. Here, we focus on eIF3, a multimeric complex with a known role in the initiation of translation and that is frequently deregulated in cancer. Our results show that the deregulated expression of eIF3e, the e subunit of eIF3, in specific GBM regions could impinge on selective protein synthesis impacting the GBM outcome. In particular, eIF3e restricts the expression of proteins involved in the response to cellular stress and increases the expression of key functional regulators of cell stemness. Such a translation program can therefore serve as a double-edged sword promoting GBM tumor growth and resistance to radiation.

scholarly journals Ribosome profiling reveals a functional role for autophagy in mRNA translational control

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Juliet Goldsmith ◽  
Timothy Marsh ◽  
Saurabh Asthana ◽  
Andrew M. Leidal ◽  
Deepthisri Suresh ◽  
...  
Keyword(s):  
Dna Damage ◽  
Protein Synthesis ◽  
Translational Control ◽  
Mammalian Cells ◽  
Dna Damage Repair ◽  
Protein Translation ◽  
Ribosome Profiling ◽  
Parp Inhibition ◽  
Genetic Ablation ◽  
Damage Repair

AbstractAutophagy promotes protein degradation, and therefore has been proposed to maintain amino acid pools to sustain protein synthesis during metabolic stress. To date, how autophagy influences the protein synthesis landscape in mammalian cells remains unclear. Here, we utilize ribosome profiling to delineate the effects of genetic ablation of the autophagy regulator, ATG12, on translational control. In mammalian cells, genetic loss of autophagy does not impact global rates of cap dependent translation, even under starvation conditions. Instead, autophagy supports the translation of a subset of mRNAs enriched for cell cycle control and DNA damage repair. In particular, we demonstrate that autophagy enables the translation of the DNA damage repair protein BRCA2, which is functionally required to attenuate DNA damage and promote cell survival in response to PARP inhibition. Overall, our findings illuminate that autophagy impacts protein translation and shapes the protein landscape.

scholarly journals Icaritin: A Novel Natural Candidate for Hematological Malignancies Therapy

2019 ◽  
Vol 2019 ◽  
pp. 1-7 ◽  
Author(s):  
Xiao-Jing Yang ◽  
Ya-Ming Xi ◽  
Zi-Jian Li
Keyword(s):  
Hematological Malignancies ◽  
Treatment Options ◽  
Chinese Herb ◽  
Cell Types ◽  
Hematologic Malignancies ◽  
Cytotoxic Effects ◽  
Novel Treatment ◽  
Traditional Chinese Herb ◽  
Current Therapies ◽  
Underlying Mechanisms

Hematological malignancies including leukemia and lymphoma can severely impact human health. With the current therapies combined with chemotherapy, stem cell transplantation, radiotherapy, and immunotherapy, the prognosis of hematologic malignancies improved significantly. However, most hematological malignancies are still incurable. Therefore, research for novel treatment options was continuing with the natural product as one source. Icaritin is a compound extracted from a traditional Chinese herb,Epimedium Genus, and demonstrated an antitumor effect in various neoplasms including hematological malignancies such as leukemia, lymphoma, and multiple myeloma. In hematological malignancies, icaritin showed multiple cytotoxic effects to induce apoptosis, arrest the cell cycle, inhibit proliferation, promote differentiation, restrict metastasis and infiltration, and suppress the oncogenic virus. The proved underlying mechanisms of the cytotoxic effects of icaritin are different in various cell types of hematological malignancies but associated with the critical cell signal pathway, including PI3K/Akt, JAK/STAT3, and MAPK/ERK/JNK. Although the primary target of icaritin is still unspecified, the existing evidence indicates that icaritin is a potential novel therapeutic agent for neoplasms as with hematological malignancies. Here, in the field of hematology, we reviewed the reported activity of icaritin in hematologic malignancies and the underlying mechanisms and recognized icaritin as a candidate for therapy of hematological malignancies.

Cancer-induced bone pain

2015 ◽  
Author(s):  
Lesley A. Colvin ◽  
Marie Fallon
Keyword(s):  
Bone Pain ◽  
Clinical Presentation ◽  
Clinical Problem ◽  
Current Therapy ◽  
Pain Mechanisms ◽  
Pain Syndromes ◽  
Current Therapies ◽  
Underlying Mechanisms ◽  
Laboratory Models ◽  
Major Clinical Problem

Bone is the third most common site of metastatic disease, after liver and lung, with approximately 75% of these patients suffering from related pain. Cancer-induced bone pain (CIBP) is a major clinical problem, with limited options for predictable, rapid, and effective treatment for some of the elements without unacceptable adverse effects. Our understanding of how current therapy acts is based mainly on studies in non-cancer pain syndromes, which are likely to be quite different, not only in clinical presentation, but also in terms of pathophysiology. It can be difficult to study the specific neurobiological changes associated with CIBP, although development of laboratory models of isolated bone metastases has allowed more specific study of pain mechanisms in this syndrome. In order to evaluate our current therapies properly and direct the development of new therapies logically, it is important to understand the underlying mechanisms of CIBP. This chapter discusses pain processing and the mechanisms and management of CIBP.

scholarly journals MicroRNAs as Emerging Regulators of Signaling in the Tumor Microenvironment

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 911 ◽  
Author(s):  
Shahzad Nawaz Syed ◽  
Bernhard Brüne
Keyword(s):  
Tumor Microenvironment ◽  
Signaling Pathways ◽  
Target Identification ◽  
Cancer Therapeutics ◽  
Protein Translation ◽  
Transcriptional Gene Silencing ◽  
Post Transcriptional Gene Silencing ◽  
Cancer Initiation ◽  
Regulate Protein

A myriad of signaling molecules in a heuristic network of the tumor microenvironment (TME) pose a challenge and an opportunity for novel therapeutic target identification in human cancers. MicroRNAs (miRs), due to their ability to affect signaling pathways at various levels, take a prominent space in the quest of novel cancer therapeutics. The role of miRs in cancer initiation, progression, as well as in chemoresistance, is being increasingly investigated. The canonical function of miRs is to target mRNAs for post-transcriptional gene silencing, which has a great implication in first-order regulation of signaling pathways. However, several reports suggest that miRs also perform non-canonical functions, partly due to their characteristic non-coding small RNA nature. Examples emerge when they act as ligands for toll-like receptors or perform second-order functions, e.g., to regulate protein translation and interactions. This review is a compendium of recent advancements in understanding the role of miRs in cancer signaling and focuses on the role of miRs as novel regulators of the signaling pathway in the TME.

C/EBPb Is a Critical Mediator of Resistance to IMiD® Immunomodulatory Compounds and Affected by IMiD Compounds Via Control of Protein Translation

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 135-135
Author(s):  
Shirong Li ◽  
Rekha Pal ◽  
Sara Monaghan ◽  
Peter Schafer ◽  
Hongjiao Ouyang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Proliferation ◽  
Cell Lines ◽  
Translational Control ◽  
Critical Role ◽  
Protein Translation ◽  
Thymidine Uptake ◽  
Double Labeling ◽  
Equity Ownership

Abstract Abstract 135 Background: Lenalidomide and pomalidomide are IMiD® immunomodulatory compounds that have been shown to be highly active in the treatment of multiple myeloma (MM). IMiD compounds exert their anti-tumor effects via acting on costimulatory proteins of T cells and NK cells, augmenting both the adaptive and innate immune system. But the mechanisms by which IMiD compounds directly inhibit MM cell proliferation are still unclear. Here we focused on the direct effects of IMiD compounds alone on MM cells. Results and Methods: We found that IMiDs, at concentrations as low as 0.01 μ M, induce significant inhibition of DNA synthesis in MM cells as shown by thymidine uptake. Since our previous work demonstrated that C/EBPβ is an important transcription factor which controls the growth and proliferation of myeloma cells, we analyzed the effects of IMiD compounds on C/EBPβ. We found that both pomalidomide and lenalidomide significantly decreased the protein level of C/EBPβ LAP-isoform in MM cell lines and primary MM cells. IMiD compound-induced suppression of C/EBPβ protein expression led to impaired transcription of the downstream IRF4, and subsequently to downregulation of BLIMP1 and XBP1, which are all critical for MM survival. To confirm our findings in vivo, we analyzed IRF4 expression by double labeling (IRF4+/CD138+) immunohistochemical staining of bone marrow biopsy samples of 23 myeloma patients prior to therapy and during therapy with lenalidomide. During lenalidomide therapy, the bone marrow MM cells showed a significantly weaker staining intensity for IRF4 in comparison to prior therapy. This was quantified by a significant (p<0.001) decrease of the staining score from 176 to 152, respectively. To confirm the critical role of C/EBPβ in MM we stably overexpressed C/EBPβ in MM cells. Overexpression of C/EBPβ prevented IMiD compound-induced inhibition of MM cell proliferation, indicating that C/EBPβ is critical in mediating resistance to IMiD compounds. This was supported by the fact that C/EBPβ was not down regulated in IMiD-resistant cell lines by IMiD treatment. Dissection of the C/EBPβ protein regulation revealed that IMiD compounds shut down C/EBPβ protein translation by decreasing eIF-4E. Knockdown experiments of eIF-4e resulted in downregulation of C/EBPβ, suggesting that C/EBPβ is under translational control in MM. Conclusions: Our studies, for the first time, provide evidence that IMiD compounds inhibit MM cell proliferation and survival by affecting the translation of C/EBPβ and subsequently multiple downstream transcription factors including IRF4, BLIMP1 and XBP1. Due to the critical role of C/EBPβ in mediating effects of IMiD compounds in MM, it might be a target to overcome drug resistance to IMiD compounds. The fact that pomalidomide can overcome resistance to lenalidomide in MM requires still further evaluation. Disclosures: Schafer: Celgene Corporation: Employment, Equity Ownership. Mapara:Gentium: Equity Ownership. Lentzsch:Celgene Corp: Research Funding.

scholarly journals Cell-free translation systems prepared from starfish oocytes faithfully reflect in vivo activity; mRNA and initiation factors stimulate supernatants from immature oocytes.

1990 ◽  
Vol 1 (13) ◽  
pp. 1057-1067 ◽  
Author(s):  
Z Xu ◽  
M B Hille
Keyword(s):  
Translational Control ◽  
Translational Regulation ◽  
High Capacity ◽  
Meiotic Maturation ◽  
Immature Oocytes ◽  
Initiation Factors ◽  
Initiation Of Translation ◽  
Free Translation ◽  
Translation Systems

Meiotic maturation stimulates a change in the translation of stored mRNAs: mRNAs encoding proteins needed for growth of oocytes are translated before meiotic maturation, whereas those encoding proteins required for cleavage are translated after meiotic maturation. Studies of translational regulation during meiotic maturation have been limited by the lack of translationally active cell-free supernatants. Starfish oocytes are ideal for preparing cell-free translation systems because experimental application of the hormone 1-methyladenine induces their maturation, synchronizing meiosis. We have prepared such systems from both immature and mature oocytes of starfish. Changes in protein synthesis rates and the specificity of proteins synthesized in these cell-free translation supernatants mimic those seen in vivo. Supernatants both from immature and mature oocytes have a high capacity to initiate new translation because 90% of the proteins made are newly initiated from mRNAs. Cell-free supernatants from mature oocytes have a much higher rate of initiation of translation than those from immature oocytes and use the 43S preinitiation complexes more efficiently in initiation of translation. Similarly, we have shown that mRNAs and initiation factors are rate limiting in cell-free translation systems prepared from immature oocytes. In addition, cell-free translation systems prepared from immature oocytes are only slightly, if at all, inhibitory to cell-free translation systems from mature oocytes. Thus, soluble inhibitors, if they exist, are rapidly converted by cell-free supernatants from mature oocytes. The similarities between translation in our starfish cell-free translation systems and in intact oocytes suggests that the cell-free translation systems will be useful tools for further studies of maturation events and translational control during meiosis.

scholarly journals HRI coordinates translation necessary for protein homeostasis and mitochondrial function in erythropoiesis

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Shuping Zhang ◽  
Alejandra Macias-Garcia ◽  
Jacob C Ulirsch ◽  
Jason Velazquez ◽  
Vincent L Butty ◽  
...  
Keyword(s):  
Iron Deficiency ◽  
Mitochondrial Function ◽  
Ribosomal Proteins ◽  
Target Genes ◽  
Mitochondrial Protein ◽  
Erythroid Differentiation ◽  
Protein Translation ◽  
Ribosome Profiling ◽  
Underlying Mechanisms

Iron and heme play central roles in the production of red blood cells, but the underlying mechanisms remain incompletely understood. Heme-regulated eIF2α kinase (HRI) controls translation by phosphorylating eIF2α. Here, we investigate the global impact of iron, heme, and HRI on protein translation in vivo in murine primary erythroblasts using ribosome profiling. We validate the known role of HRI-mediated translational stimulation of integratedstressresponse mRNAs during iron deficiency in vivo. Moreover, we find that the translation of mRNAs encoding cytosolic and mitochondrial ribosomal proteins is substantially repressed by HRI during iron deficiency, causing a decrease in cytosolic and mitochondrial protein synthesis. The absence of HRI during iron deficiency elicits a prominent cytoplasmic unfolded protein response and impairs mitochondrial respiration. Importantly, ATF4 target genes are activated during iron deficiency to maintain mitochondrial function and to enable erythroid differentiation. We further identify GRB10 as a previously unappreciated regulator of terminal erythropoiesis.

scholarly journals Single-Cell RNA Sequencing Reveals Endothelial Cell Transcriptome Heterogeneity under Homeostatic Laminar Flow

2020 ◽  
Author(s):  
Ziqing Liu ◽  
Dana L Ruter ◽  
Kaitlyn Quigley ◽  
Yuchao Jiang ◽  
Victoria L Bautch
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Laminar Flow ◽  
Single Cell ◽  
Rna Sequencing ◽  
Protein Translation ◽  
Flow Conditions ◽  
Expression Levels ◽  
Cell Behaviors ◽  
Single Cell Rna Sequencing

ABSTRACTObjectiveEndothelial cells that form the innermost layer of all vessels exhibit heterogeneous cell behaviors and responses to pro-angiogenic signals that are critical for vascular sprouting and angiogenesis. Once vessels form, remodeling and blood flow lead to endothelial cell quiescence, and homogeneity in cell behaviors and signaling responses. These changes are important for the function of mature vessels, but whether and at what level endothelial cells regulate overall expression heterogeneity during this transition is poorly understood. Here we profiled endothelial cell transcriptomic heterogeneity, and expression heterogeneity of selected proteins, under homeostatic laminar flow.Approach and ResultsSingle-cell RNA sequencing and fluorescence microscopy were used to characterize heterogeneity in RNA and protein gene expression levels of human endothelial cells under homeostatic laminar flow compared to non-flow conditions. Analysis of transcriptome variance, Gini coefficient, and coefficient of variation showed that more genes increased RNA heterogeneity under laminar flow relative to genes whose expression became more homogeneous. Analysis of a subset of genes for relative protein expression revealed that most protein profiles showed decreased heterogeneity under flow. In contrast, the magnitude of expression level changes in RNA and protein was coordinated among endothelial cells in flow vs. non-flow conditions.ConclusionsEndothelial cells exposed to homeostatic laminar flow showed increased cohort heterogeneity in RNA expression levels, while cohort expression heterogeneity of selected cognate proteins decreased under laminar flow. These findings suggest that EC homeostasis is imposed at the level of protein translation and/or stability rather than transcriptionally.

scholarly journals How to Uncover Sources of Unwarranted Practice Variation: A Case Study in Emergency Medicine

2018 ◽  
Vol 28 (9) ◽  
pp. 1486-1498 ◽  
Author(s):  
Markus A. Feufel
Keyword(s):  
Emergency Medicine ◽  
Care Delivery ◽  
Practice Variation ◽  
Emergency Physicians ◽  
Unmet Expectations ◽  
Variation In Care ◽  
Medical Need ◽  
Equity And Efficiency ◽  
Underlying Mechanisms

Forty years of statistical database analyses have demonstrated the existence of unwarranted practice variation in care delivery, that is, variations independent of medical need, evidence, or patient preference. Alas, little is known about the underlying mechanisms and thus finding interventions to reduce unwarranted variations remains difficult, hampering quality, equity, and efficiency of care. Whereas statistical analyses describe deviations from ideal patterns, ethnographically inspired analyses aim at understanding when, how, and why variations occur in practice. Based on case studies derived from shadowing emergency physicians, I demonstrate that analyzing practice variation in practice helps to (a) advance the understanding of mechanisms and (b) evaluate/expand the existing repertoire of interventions. Results revealed unmet expectations and new sources of known variations as well as interventions complementing systemic changes with those that empower individuals to better cope with the existing system. These findings highlight the benefits of mixed-methods for understanding and tackling practice variation.

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