This review will summarise the recent discoveries and current state of research on short noncoding RNAs derived from tRNAs-known as tRNA-derived fragments (tRFs). It will describe the features of the ...known subtypes of these RNAs; including sequence characteristics, protein interactors, expression characteristics, biogenesis, and similarity to canonical miRNA pathways. Also their role in regulating gene expression; including mediating translational suppression, will be discussed. We also highlight their potential use as biomarkers, functions in gene regulation and links to disease. Finally, this review will speculate as to the origin and rationale for the conservation of this novel class of noncoding RNAs amongst both prokaryotes and eukaryotes.
Spatial proteomics technologies have revealed an underappreciated link between the location of cells in tissue microenvironments and the underlying biology and clinical features, but there is ...significant lag in the development of downstream analysis methods and benchmarking tools. Here we present SPIAT (spatial image analysis of tissues), a spatial-platform agnostic toolkit with a suite of spatial analysis algorithms, and spaSim (spatial simulator), a simulator of tissue spatial data. SPIAT includes multiple colocalization, neighborhood and spatial heterogeneity metrics to characterize the spatial patterns of cells. Ten spatial metrics of SPIAT are benchmarked using simulated data generated with spaSim. We show how SPIAT can uncover cancer immune subtypes correlated with prognosis in cancer and characterize cell dysfunction in diabetes. Our results suggest SPIAT and spaSim as useful tools for quantifying spatial patterns, identifying and validating correlates of clinical outcomes and supporting method development.
The functionality of small RNAs from abundant species of “housekeeping” noncoding RNAs (e.g., rRNA, tRNA, snRNA, snoRNA, etc.) remains a highly studied topic. The current state of research on short ...RNAs derived from transfer RNA (tRNA), called tRNA-derived fragments (tRFs), has been restricted largely to expression studies and limited functional studies. 5′ tRFs are known translational inhibitors in mammalian cells, yet little is known about their functionality. Here we report on the first experimental evidence of the tRF protein interactome, identifying the mammalian multisynthetase complex as the primary interactor of the 5′ tRF Gln19. We also present proteome-wide SILAC evidence that 5′ tRFs increase ribosomal and poly(A)-binding protein translation.
Abstract
Since its discovery, the E3 ubiquitin ligase E6-associated protein (E6AP) has been studied extensively in two pathological contexts: infection by the human papillomavirus (HPV), and the ...neurodevelopmental disorder, Angelman syndrome. Vital biological links between E6AP and other viruses, namely hepatitis C virus and encephalomyocarditis virus, have been recently uncovered. Critically, oncogenic E6AP activities have been demonstrated to contribute to cancers of both viral and non-viral origins. HPV-associated cancers serve as the primary example of E6AP involvement in cancers driven by viruses. Studies over the past few years have exposed a role for E6AP in non-viral-related cancers. This has been demonstrated in B-cell lymphoma and prostate cancers, where oncogenic E6AP functions drive these cancers by acting on key tumour suppressors. In this review we discuss the role of E6AP in viral infection, viral propagation and viral-related cancer. We discuss processes affected by oncogenic E6AP, which promote cancers of viral and non-viral aetiology. Overall, recent findings support the role of oncogenic E6AP in disrupting key cellular processes, including tumour suppression and the immune response. E6AP is consequently emerging as an attractive therapeutic target for a number of specific cancers.
E6AP has been demonstrated to contribute to cancers of both viral and non-viral origin. In this review we discuss the role of E6AP and its involvement in viral infection, viral propagation, and viral related cancers.
The long and the short of it: the MDM4 tail so far Haupt, Sue; Mejía-Hernández, Javier Octavio; Vijayakumaran, Reshma ...
Journal of molecular cell biology,
03/2019, Letnik:
11, Številka:
3
Journal Article
Recenzirano
Odprti dostop
The mouse double minute 4 (MDM4) is emerging from the shadow of its more famous relative MDM2 and is starting to steal the limelight, largely due to its therapeutic possibilities. MDM4 is a vital ...regulator of the tumor suppressor p53. It restricts p53 transcriptional activity and also, at least in development, facilitates MDM2's E3 ligase activity toward p53. These functions of MDM4 are critical for normal cell function and a proper response to stress. Their importance for proper cell maintenance and proliferation identifies them as a risk for deregulation associated with the uncontrolled growth of cancer. MDM4 tails are vital for its function, where its N-terminus transactivation domain engages p53 and its C-terminus RING domain binds to MDM2. In this review, we highlight recently identified cellular functions of MDM4 and survey emerging therapies directed to correcting its dysregulation in disease.
Patients with refractory relapsed multiple myeloma respond to combination treatment with elotuzumab and lenalidomide. The mechanisms underlying this observation are not fully understood. Furthermore, ...biomarkers predictive of response have not been identified to date. To address these issues, we used a humanized myeloma mouse model and adoptive transfer of human natural killer (NK) cells to show that elotuzumab and lenalidomide treatment controlled myeloma growth, and this was mediated through CD16 on NK cells. In co-culture studies, we showed that peripheral blood mononuclear cells from a subset of patients with refractory relapsed multiple myeloma were effective killers of OPM2 myeloma cells when treated with elotuzumab and lenalidomide, and this was associated with significantly increased expression of CD54 on OPM2 cells. Furthermore, elotuzumab- and lenalidomide-induced OPM2 cell killing and increased OPM2 CD54 expression were dependent on both monocytes and NK cells, and these effects were not mediated by soluble factors alone. At the transcript level, elotuzumab and lenalidomide treatment significantly increased OPM2 myeloma cell expression of genes for trafficking and adhesion molecules, NK cell activation ligands and antigen presentation molecules. In conclusion, our findings suggest that multiple myeloma patients require elotuzumab- and lenalidomide-mediated upregulation of CD54 on autologous myeloma cells, in combination with NK cells and monocytes to mediate an effective anti-tumor response. Furthermore, our data suggest that increased myeloma cell CD54 expression levels could be a powerful predictive biomarker for response to elotuzumab and lenalidomide treatment.
Abstract Objective Parental obesity can induce metabolic phenotypes in offspring independent of the inherited DNA sequence. Here we asked whether such non-genetic acquired metabolic traits can be ...passed on to a second generation that has never been exposed to obesity, even as germ cells. Methods We examined the F1, F2, and F3 a / a offspring derived from F0 matings of obese prediabetic A vy / a sires and lean a / a dams. After F0, only lean a / a mice were used for breeding. Results We found that F1 sons of obese founder males exhibited defects in glucose and lipid metabolism, but only upon a post-weaning dietary challenge. F1 males transmitted these defects to their own male progeny (F2) in the absence of the dietary challenge, but the phenotype was largely attenuated by F3. The sperm of F1 males exhibited changes in the abundance of several small RNA species, including the recently reported diet-responsive tRNA-derived fragments. Conclusions These data indicate that induced metabolic phenotypes may be propagated for a generation beyond any direct exposure to an inducing factor. This non-genetic inheritance likely occurs via the actions of sperm noncoding RNA.
Lung cancer poses the greatest cancer-related death risk and males have poorer outcomes than females, for unknown reasons. Patient sex is not a biological variable considered in lung cancer standard ...of care. Correlating patient genetics with outcomes is predicted to open avenues for improved management. Using a bioinformatics approach across non-small cell lung cancer (NSCLC) subtypes, we identified where patient sex, mutation of the major tumor suppressor gene, Tumour protein P53 (TP53), and immune signatures stratified outcomes in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), among datasets of The Cancer Genome Atlas (TCGA). We exposed sex and TP53 gene mutations as prognostic for LUAD survival. Longest survival in LUAD occurred among females with wild-type (wt) TP53 genes, high levels of immune infiltration and enrichment for pathway signatures of Interferon Gamma (INF-γ), Tumour Necrosis Factor (TNF) and macrophages-monocytes. In contrast, poor survival in men with LUAD and wt TP53 genes corresponded with enrichment of Transforming Growth Factor Beta 1 (TGFB1, hereafter TGF-β) and wound healing signatures. In LUAD with wt TP53 genes, elevated gene expression of immune checkpoint CD274 (hereafter: PD-L1) and also protein 53 (p53) negative-regulators of the Mouse Double Minute (MDM)-family predict novel avenues for combined immunotherapies. LUSC is dominated by male smokers with TP53 gene mutations, while a minor population of TCGA LC patients with wt TP53 genes unexpectedly had the poorest survival, suggestive of a separate etiology. We conclude that advanced approaches to LUAD and LUSC therapy lie in the consideration of patient sex, TP53 gene mutation status and immune signatures.
We describe here a protocol to measure gene expression, T cell receptor (TCR) sequence, and protein expression by single T cells extracted from melanoma, using 10× Chromium technology. This method ...includes freezing and thawing of the melanoma infiltrating lymphocytes, staining of cells with fluorescent and barcode-conjugated antibodies, sorting of T cells, and loading the cells on the 10× Chromium Controller. After sequencing, analysis includes quality control, genetic demultiplexing to resolve genetically different samples, and T cell clonality and clustering analysis. Single cell RNA sequencing paints the complete portrait of individual T cells, including their clonality and phenotype, and it reconstructs a complete picture of the T cell infiltrate in a tumor that is represented as cell clustering similar to a pointillism painting.
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