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Oxygen and nutrient deprivation are common features of solid tumors. Although abnormal alternative splicing (AS) has been found to be an important driving force in tumor pathogenesis and progression, the regulatory mechanisms of AS that underly the adaptation of cancer cells to harsh microenvironments remain unclear. Here, we found that hypoxia- and nutrient deprivation-induced asparagine endopeptidase (AEP) specifically cleaved DDX3X in a HIF1A-dependent manner. This cleavage yields truncated carboxyl-terminal DDX3X (tDDX3X-C), which translocates and aggregates in the nucleus. Unlike intact DDX3X, nuclear tDDX3X-C complexes with an array of splicing factors and induces AS events of many premRNAs; for example, enhanced exon skipping (ES) in exon 2 of the classic tumor suppressor PRDM2 leads to a frameshift mutation of PRDM2. Intriguingly, the isoform ARRB1-[DELTA]exon 13 binds to glycolytic enzymes and regulates glycolysis. By utilizing in vitro assays, glioblastoma organoids, and animal models, we revealed that AEP/tDDX3X-C promoted tumor malignancy via these isoforms. More importantly, high AEP/tDDX3X-C/ARRB1- [DELTA]exon 13 in cancerous tissues was tightly associated with poor patient prognosis. Overall, our discovery of the effect of AEP-cleaved DDX3X switching on alternative RNA splicing events identifies a mechanism in which cancer cells adapt to oxygen and nutrient shortages and provides potential diagnostic and/or therapeutic targets., Introduction In the tumor microenvironment, cells often face a certain degree of oxygen and nutrient deprivation. Cancer cells strive to survive and proliferate in this harsh environment in multiple ways, [...]

Background: As an adult tumor with the most invasion and the highest mortality rate, the inherent heterogeneity of glioblastoma (GBM) is the main factor that causes treatment failure. Therefore, it is important to have a deeper understanding of the pathology of GBM. Some studies have shown that Eukaryotic Initiation Factor 4A-3 (EIF4A3) can promote the growth of many people's tumors, and the role of specific molecules in GBM remains unclear. Methods: The correlation between the expression of EIF4A3 gene and its prognosis was studied in 94 GBM patients using survival analysis. Further in vitro and in vivo experiments, the effect of EIF4A3 on GBM cells proliferation, migration, and the mechanism of EIF4A3 on GBM was explored. In addition, combined with bioinformatics analysis, we further confirmed that EIF4A3 contributes to the progress of GBM. Results: The expression of EIF4A3 was upregulated in GBM tissues, and high expression of EIF4A3 is associated with poor prognosis in GBM. In vitro, knockdown of EIF4A3 significantly reduced the proliferation, migration, and invasion abilities of GBM cells, whereas overexpression of EIF4A3 led to the opposite effect. The analysis of differentially expressed genes related to EIF4A3 indicates that it is involved in many cancer-related pathways, such as Notch and JAK-STAT3 signal pathway. In Besides, we demonstrated the interaction between EIF4A3 and Notch1 by RNA immunoprecipitation. Finally, the biological function of EIF4A3-promoted GBM was confirmed in living organisms. Conclusion: The results of this study suggest that EIF4A3 may be a potential prognostic factor, and Notch1 participates in the proliferation and metastasis of GBM cells mediated by EIF4A3. [ABSTRACT FROM AUTHOR]

Yield is the most important and complex trait for the genetic improvement of crops. Although much research into the genetic basis of yield and yield-associated traits has been reported, in each such experiment the genetic architecture and determinants of yield have remained ambiguous. One of the most intractable problems is the interaction between genes and the environment. We identified 85 quantitative trait loci (QTL) for seed yield along with 785 QTL for eight yield-associated traits, from 10 natural environments and two related populations of rapeseed. A trait-by-trait meta-analysis revealed 401 consensus QTL, of which 82.5% were clustered and integrated into 111 pleiotropic unique QTL by metaanalysis, 47 of which were relevant for seed yield. The complexity of the genetic architecture of yield was demonstrated, illustrating the pleiotropy, synthesis, variability, and plasticity of yield QTL. The idea of estimating indicator QTL for yield QTL and identifying potential candidate genes for yield provides an advance in methodology for complex traits. DOI: 10.1534/genetics.109.101642

Rapeseed (Brassica napus L.) is one of the most important oilseed crops both in Europe and in China. The objective of this study was to investigate whether the European and the Chinese gene pools of winter oilseed rape contain different alleles for high seed oil content. A linkage map of rapeseed comprising 125 SSR markers and covering 1196-cM genome length was constructed from an [F.sub.1] derived doubled haploid (DH) population from a cross between the German cultivar Sollux and the Chinese cultivar Gaoyou, both selected for high oil content. In total, 282 DH lines were evaluated in replicated field experiments in four environments, two each in Germany and in China. QTL were mapped and their additive and epistatic effects as well as interactions with environments were estimated by a mixed model approach implemented in the mapping software QTLMapper. Eight QTL with additive effects and nine pairs of loci with additive x additive epistasis were detected, which together accounted for 80% of the phenotypic variation. The alleles increasing oil content were dispersed between the parents, which explained the transgressive segregation observed: seven DH lines surpassed the better parent by more than 3% oil content. Five of the eight QTL with additive effects showed significant genotype x environment interactions, and 10 additional QTL with genotype x environment interactions, but no significant additive main effect were observed. Epistatic interactions mainly occurred between QTL which also showed additive effects or additive x environment interactions. In conclusion, a marker assisted selection to recombine positive alleles from European and Chinese material is a powerful approach to further increase the oil content of rapeseed, but epistatic effects and genotype x environment interactions have to be considered., THE MOST IMPORTANT traits in oilseed breeding are seed yield and seed oil content. Whereas seed yield is an extremely complex character, seed oil content might be a suitable trait [...]