The cell stress response: extreme times call for post-transcriptional measures.

Following cell stress, a wide range of molecular pathways are initiated to orchestrate the stress response and enable adaptation to an environmental or intracellular perturbation. The post-transcriptional regulation strategies adopted during the stress response result in a substantial reorganization of gene expression, designed to prepare the cell for either acclimatization or programmed death, depending on the nature and intensity of the stress. Fundamental to the stress response is a rapid repression of global protein synthesis, commonly mediated by phosphorylation of translation initiation factor eIF2α. Recent structural and biochemical information have added unprecedented detail to our understanding of the molecular mechanisms underlying this regulation. During protein synthesis inhibition, the translation of stress-specific mRNAs is nonetheless enhanced, often through the interaction between RNA-binding proteins and specific RNA regulatory elements. Recent studies investigating the unfolded protein response (UPR) provide some important insights into how posttranscriptional events are spatially and temporally fine-tuned in order to elicit the most appropriate response and to coordinate the transition from an early, acute stage into the chronic state of adaptation. Importantly, cancer cells are known to hi-jack adaptive stress response pathways, particularly the UPR, to survive and proliferate in the unfavorable tumor environment. In this review, we consider the implications of recent research into stress-dependent post-transcriptional regulation and make the case for the exploration of the stress response as a strategy to identify novel targets in the development of cancer therapies. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Evolution and Genomics > RNA and Ribonucleoprotein Evolution Translation > Translation Mechanisms > Translation Regulation

The pathogenesis of mesothelioma is driven by a dysregulated translatome.

Funder: Department of HealthMalignant mesothelioma (MpM) is an aggressive, invariably fatal tumour that is causally linked with asbestos exposure. The disease primarily results from loss of tumour suppressor gene function and there are no 'druggable' driver oncogenes associated with MpM. To identify opportunities for management of this disease we have carried out polysome profiling to define the MpM translatome. We show that in MpM there is a selective increase in the translation of mRNAs encoding proteins required for ribosome assembly and mitochondrial biogenesis. This results in an enhanced rate of mRNA translation, abnormal mitochondrial morphology and oxygen consumption, and a reprogramming of metabolic outputs. These alterations delimit the cellular capacity for protein biosynthesis, accelerate growth and drive disease progression. Importantly, we show that inhibition of mRNA translation, particularly through combined pharmacological targeting of mTORC1 and 2, reverses these changes and inhibits malignant cell growth in vitro and in ex-vivo tumour tissue from patients with end-stage disease. Critically, we show that these pharmacological interventions prolong survival in animal models of asbestos-induced mesothelioma, providing the basis for a targeted, viable therapeutic option for patients with this incurable disease

Social impacts as a function of place change

This paper argues that both impacts felt by and attitudes to tourism are a function of place change. Destinations are comprised of three types of place: tourism, non-tourism and shared. It is believed attitudes are generally positive when stasis exists among the three types, but deteriorate during periods of rapid place change. Likewise, impacts are felt when place changes, especially when non-tourism place is transformed into either shared or tourism place. This proposition is tested through a meta-analysis of more than 90 journal articles examining social impacts of tourism. Nine types of place change were identified as well as a relationship between place change and lifecycle stage

Schuldig landschap. Over de toeristische aantrekkingskracht van Baantjer, Wallander en Inspector Morse

De opnamelokaties van tv-detectives genieten een toenemende populariteit onder toeristen. In dit artikel wordt, op basis van een tekstuele analyse van ‘Baantjer’, ‘Inspector Morse’ en ‘Wallander’, onderzocht welke inhoudelijke kenmerken van deze tv-detectives mogelijk als ‘trigger’ fungeren. Uit de analyse blijkt dat plaats en beweging een centrale rol vervullen binnen de narratieve structuur van dit genre. Door zelf de lokaties te bezoeken, kunnen toeristen het spoor nalopen van hun geliefde detective om aldaar, vanuit een veilige positie, tijdelijk op te gaan in het schemergebied tussen fictie en werkelijkheid

Plant-arthropod interactions: who is the winner?

Herbivorous arthropods have interacted with plants for millions of years. During feeding they release chemical cues that allow plants to detect the attack and mount an efficient defense response. A signaling cascade triggers the expression of hundreds of genes, which encode defensive proteins and enzymes for synthesis of toxic metabolites. This direct defense is often complemented by emission of volatiles that attract beneficial parasitoids. In return, arthropods have evolved strategies to interfere with plant defenses, either by producing effectors to inhibit detection and downstream signaling steps, or by adapting to their detrimental effect. In this review, we address the current knowledge on the molecular and chemical dialog between plants and herbivores, with an emphasis on co-evolutionary aspects

The identification and characterisation of novel cytoplasmic ASC-1 complex protein interactions

Cytoplasmic control of gene expression allows for a rapid reprogramming of specific cellular processes in response to stresses, such as exposure to agents that damage nucleic acids. These responses dictate cell fate in the absence of transcriptional regulation, by regulating the expression of proteins that permit a cell to promote cell survival pathways, or alternatively trigger cell death in situations where homeostasis cannot be restored. In general, cytoplasmic control of gene expression is achieved by the action of RNA-binding proteins, therefore, techniques that allow the analysis of the RNA-bound proteome, such as RNA-interactome capture (RIC), permit the identification of novel RNA-binding proteins (RBPs) that have a key regulatory role in these responses. Work within the Willis laboratory has previously identified Activating signal cointegrator 1 (ASC-1) complex subunit 3 (ASCC3) as a cytoplasmic protein that has increased affinity for RNA in response to UVB irradiation. ASCC3 is a member of the ASC-1 complex, which also includes ASCC2, TRIP4, and ASCC1.In this thesis, the ASC-1 complex members were investigated using immunoaffinity purification and size exclusion chromatography-based approaches. The data show that ASCC3 has increased binding to RNA in a range of cell lines following exposure to UVB and 4NQO, and that the response of ASCC3 and the ASC-1 complex to nucleic acid damage is conserved. FLAG-tagged versions of ASCC3 were generated, and when used as a bait in immunoaffinity purification reactions, the deubiquitinase OTUD4 was identified as a novel interactor of ASCC3. Further studies showed that OTUD4 was part of the cytoplasmic ASC-1 complex, although this interaction may occur with only a small proportion of total cytoplasmic OTUD4. While OTUD4 did not influence control of global protein synthesis rates or cell proliferation, it demonstrated increased binding to polyribosomes following treatment of cells with 4NQO, suggesting that it may function in the ribosome quality control pathway.</div

Full-length NF-κB repressing factor contains an XRN2 binding domain.

NF-κB repressing factor (NKRF) was recently identified as an RNA binding protein that together with its associated proteins, the 5'-3' exonuclease XRN2 and the helicase DHX15, is required to process the precursor ribosomal RNA. XRN2 is a multi-functional ribonuclease that is also involved in processing mRNAs, tRNAs and lncRNAs. The activity and stability of XRN2 are controlled by its binding partners, PAXT-1, CDKN2AIP and CDKN2AIPNL. In each case, these proteins interact with XRN2 via an XRN2 binding domain (XTBD), the structure and mode of action of which is highly conserved. Rather surprisingly, although NKRF interacts directly with XRN2, it was not predicted to contain such a domain, and NKRF's interaction with XRN2 was therefore unexplained. We have identified an alternative upstream AUG start codon within the transcript that encodes NKRF and demonstrate that the full-length form of NKRF contains an XTBD that is conserved across species. Our data suggest that NKRF is tethered in the nucleolus by binding directly to rRNA and that the XTBD in the N-terminal extension of NKRF is essential for the retention of XRN2 in this sub-organelle. Thus, we propose NKRF regulates the early steps of pre-rRNA processing during ribosome biogenesis by controlling the spatial distribution of XRN2 and our data provide further support for the XTBD as an XRN2 interacting motif