Equol,an Isoflavone Metabolite,Regulates Cancer Cell Viability and Protein Synthesis Initiation via c-Myc and eIF4G

Epidemiological studies implicate dietary soy isoflavones as breast cancer preventives, especially due to their anti-estrogenic properties. However, soy isoflavones may also have a role in promoting breast cancer, which has yet to be clarified. We previously reported that equol, a metabolite of the soy isoflavone daidzein, may advance breast cancer potential via up-regulation of the eukaryotic initiation factor 4GI (eIF4GI). In estrogen receptor negative (ER−) metastatic breast cancer cells, equol induced elevated levels of eIF4G, which were associated with increased cell viability and the selective translation of mRNAs that use non-canonical means of initiation, including internal ribosome entry site (IRES), ribosome shunting, and eIF4G enhancers. These mRNAs typically code for oncogenic, survival, and cell stress molecules. Among those mRNAs translationally increased by equol was the oncogene and eIF4G enhancer, c-Myc. Here we report that siRNA-mediated knockdown of c-Myc abrogates the increase in cancer cell viability and mammosphere formation by equol, and results in a significant down-regulation of eIF4GI (the major eIF4G isoform), as well as reduces levels of some, but not all, proteins encoded by mRNAs that are translationally stimulated by equol treatment. Knockdown of eIF4GI also markedly reduces an equol-mediated increase in IRES-dependent mRNA translation and the expression of specific oncogenic proteins. However, eIF4GI knockdown did not reciprocally affect c-Myc levels or cell viability. This study therefore implicates c-Myc as a potential regulator of the cancer-promoting effects of equol via up-regulation of eIF4GI and selective initiation of translation on mRNAs that utilize non-canonical initiation, including certain oncogenes.     

组蛋白赖氨酸特异性去甲基化酶1A在肿瘤发生发展中的作用

组蛋白赖氨酸特异性去甲基化酶1A (Histone lysine-specific demethylase 1A,KDM1A)作为组蛋白赖氨酸特异性去甲基化酶(Histonelysine-specificdemethylase)家族的一员,在信号传导、染色体重构、胚胎发育、造血和糖脂代谢等生物学过程中起着重要的作用。近年来的研究及临床证据表明,KDM1A的表达与肿瘤的发生发展密不可分,通过与不同的复合物结合并介导不同的下游信号通路,对多种肿瘤的生长增殖起着关键的调节作用,例如前列腺癌、乳腺癌、肺癌和肝癌等。在大多数情况下,KDM1A在肿瘤的发生发展中扮演着促癌基因角色。文中结合近年来有关文献,阐述了KDM1A在多种肿瘤发生及发展中的研究进展,总结了其作用机制,并对以KDM1A为靶点的抑癌治疗的应用前景进行了展望。     

Inadequate pollination services limit watermelon yields in northern Tanzania

Insect pollination plays a vital role for the yield of many crops, such as apples, strawberries and coffee, which are economically significant commodities on the global market. Yet, knowledge about the role of insect pollination is lacking for many cash crops that support the livelihoods of small-scale farmers in developing countries.To assess if yields of watermelon are pollen limited, we conducted a supplemental hand-pollinated experiment (using a pollen mixture of cross and self-pollen) in 13 small-scale farms in an agricultural landscape in the Kilimanjaro and Arusha regions in northern Tanzania. We assessed fruit set, fruit abortion and weight of the mature fruits stemming from hand pollinated and control flowers. To check if differences in yield responses between hand-pollinated and control treatments depended on resource availability, we also accounted for local soil conditions.We found that hand pollination (i) increased the probability of fruit initiation by 30%, (ii) reduced the probability of fruit abortion by 13%, (iii) increased the probability of flowers developing into mature fruits by 42% and (iv) increased average fruit weight by 1.3 kg (±0.15 SE). Our results indicate that our system is pollen limited, due to insufficient visitor frequency and/or inefficient pollinator species.Fruit initiation and fruit weight were positively related to soil carbon, irrespective of treatment. The influence of soil moisture was not consistent across the measured responses, and differed between hand-pollinated and the control treatments.We suggest that farmers in our focal area should focus on improving the quality of the landscape to sustain and enhance healthy pollinator communities ultimately improving yields. We also suggest that farmers should continue current practices with respect to fertilization. The role of soil moisture on fruit initiation and maturation should be investigated to ensure that the positive effects of pollen is not hindered by soil moisture conditions.     

Behavioral responses of nesting birds to human disturbance along recreational trails

ABSTRACT The presence of recreational trails can impact breeding birds either indirectly by altering habitat or the movement patterns of predators or directly if the presence of humans disturbs birds. We examined the behavioral responses of nesting female Northern Cardinals (Cardinalis cardinalis) to human disturbance using both experimental and observational approaches. From April to August 2006 and 2007, we monitored Northern Cardinal nests in 18 riparian forests in Ohio, USA. Two experimental trials were conducted at each nest (N= 63), with Flight Initiation Distance (FID, the distance at which a bird flushed from the nest) recorded as we approached nests by walking directly toward them and by walking along trails located variable distances from nests. We also measured flight initiation distance (FID) when nests were approached during routine nest checks (N= 160). Cardinals were six times more likely to flush when nests were approached directly, and females on higher nests were less likely to flush regardless of distance to trail. FID was not significantly influenced by the distance of nests from trails. We found no association between nest survival and the tendency of birds to flush. Rather, nest survival was best explained by nest height. Thus, our findings suggest that the responses of birds to human use of recreational trails have only short‐term effects, with no apparent effects of on nest survival. Because the reaction of birds to humans in our study depended on how nests were approached, studies where FID is used as an indicator of sensitivity to human disturbance and is determined by direct approaches may overestimate the potential impact of trails on nesting birds.     

Coordination between plant and apex development in Hordeum vulgare ssp. distichum

Developmental scales for cereals describe apex and plant morphology separately. In order to link crucial steps of internal and external development, in three varieties of Hordeum vulgare spp. distichum L., sown in autumn and in spring, we recorded plant, leaf and apex stage, following the scales of Zadoks, Haun, and Banerjee and Wienhues, the number of primordia, culm and spike length, and the final number of leaves and spikelets. Primordia initiation was coordinated with leaf appearance and the relative rate was constant for the initiation of productive primordia. The maximum number of primordia was achieved just before the first node became detectable, but development was completed only by those initiated before floret differentiation and internode distension started. The first spikelet was initiated when the third leaf tip became visible, and the last one when plants were at the pseudo stem erection stage and five leaves had still to appear.     

Prednisolone-induced beta cell dysfunction is associated with impaired endoplasmic reticulum homeostasis in INS-1E cells

Glucocorticoids (GCs), such as prednisolone (PRED), are widely prescribed anti-inflammatory drugs, but their use may induce glucose intolerance and diabetes. GC-induced beta cell dysfunction contributes to these diabetogenic effects through mechanisms that remain to be elucidated. In this study, we hypothesized that activation of the unfolded protein response (UPR) following endoplasmic reticulum (ER) stress could be one of the underlying mechanisms involved in GC-induced beta cell dysfunction. We report here that PRED did not affect basal insulin release but time-dependently inhibited glucose-stimulated insulin secretion in INS-1E cells. PRED treatment also decreased both PDX1 and insulin expression, leading to a marked reduction in cellular insulin content. These PRED-induced detrimental effects were found to be prevented by prior treatment with the glucocorticoid receptor (GR) antagonist RU486 and associated with activation of two of the three branches of the UPR. Indeed, PRED induced a GR-mediated activation of both ATF6 and IRE1/XBP1 pathways but was found to reduce the phosphorylation of PERK and its downstream substrate eIF2α. These modulations of ER stress pathways were accompanied by upregulation of calpain 10 and increased cleaved caspase 3, indicating that long term exposure to PRED ultimately promotes apoptosis. Taken together, our data suggest that the inhibition of insulin biosynthesis by PRED in the insulin-secreting INS-1E cells results, at least in part, from a GR-mediated impairment in ER homeostasis which may lead to apoptotic cell death.     

Bypassing of stems versus linear base-by-base inspection of mammalian mRNAs during ribosomal scanning

Initiation codon selection in eukaryotes involves base-by-base inspection of the 5'-untranslated region of mRNA by scanning ribosomal 43S preinitiation complexes. We employed in vitro reconstitution to investigate factor requirements for this process and report that in the absence of eIF1 and DHX29, eIFs 4A, 4B and 4G promote efficient bypassing of stable stems by scanning 43S complexes and formation of 48S initiation complexes on AUG codons immediately upstream and downstream of such stems, without their unwinding. However, intact stems are not threaded through the entire mRNA Exit channel of the 40S subunit, resulting in incorrect positioning of mRNA upstream of the ribosomal P site in 48S complexes formed on AUG codons following intact stems, which renders them susceptible to dissociation by eIF1. In 48S complexes formed on AUG codons preceding intact stems, the stems are accommodated in the A site. Such aberrant complexes are destabilized by DHX29, which also ensures that mRNA enters the mRNA-binding cleft in a single-stranded form and therefore undergoes base-by-base inspection during scanning.