Heterogeneous nuclear ribonucleoproteins (hnRNPs) comprise a family of RNA-binding proteins. The complexity and diversity associated with the hnRNPs render them multifunctional, involved not only in ...processing heterogeneous nuclear RNAs (hnRNAs) into mature mRNAs, but also acting as trans-factors in regulating gene expression. Heterogeneous nuclear ribonucleoprotein E1 (hnRNP E1), a subgroup of hnRNPs, is a KH-triple repeat containing RNA-binding protein. It is encoded by an intronless gene arising from hnRNP E2 through a retrotransposition event. hnRNP E1 is ubiquitously expressed and functions in regulating major steps of gene expression, including pre-mRNA processing, mRNA stability, and translation. Given its wide-ranging functions in the nucleus and cytoplasm and interaction with multiple proteins, we propose a post-transcriptional regulon model that explains hnRNP E1's widespread functional diversity.
Transcript-selective translational regulation of epithelial-mesenchymal transition (EMT) by transforming growth factor-β (TGF-β) is directed by the hnRNP E1-containing TGF-β-activated-translational ...(BAT) mRNP complex. Herein, eukaryotic elongation factor-1 A1 (eEF1A1) is identified as an integral component of the BAT complex. Translational silencing of Dab2 and ILEI, two EMT transcripts, is mediated by the binding of hnRNP E1 and eEF1A1 to their 3′UTR BAT element, whereby hnRNP E1 stalls translational elongation by inhibiting the release of eEF1A1 from the ribosomal A site. TGF-β-mediated hnRNP E1 phosphorylation, through Akt2, disrupts the BAT complex, thereby restoring translation of target EMT transcripts. Attenuation of hnRNP E1 expression in two noninvasive breast epithelial cells (NMuMG and MCF-7) not only induced EMT but also enabled cells to form metastatic lesions in vivo. Thus, translational regulation by TGF-β at the elongation stage represents a critical checkpoint coordinating the expression of EMT transcripts required during development and in tumorigenesis and metastatic progression.
► eEF1A1 and hnRNP E1 coordinate translational repression of EMT-inducer transcripts ► eEF1A1/hnRNP E1 interactions block translation at the elongation stage ► hnRNP E1 phosphorylation by TGF-β/Akt2 relieves translational repression ► Attenuation of hnRNP E1 expression results in EMT, tumorigenesis, and metastasis
In order to better understand the process of breast cancer metastasis, we have generated a mammary epithelial progression series of increasingly aggressive cell lines that metastasize to lung. Here ...we demonstrate that upregulation of an endoplasmic reticulum (ER) to Golgi trafficking gene signature in metastatic cells enhances transport kinetics, which promotes malignant progression. We observe increased ER-Golgi trafficking, an altered secretome and sensitivity to the retrograde transport inhibitor brefeldin A (BFA) in cells that metastasize to lung. CREB3 was identified as a transcriptional regulator of upregulated ER-Golgi trafficking genes ARF4, COPB1, and USO1, and silencing of these genes attenuated the metastatic phenotype in vitro and lung colonization in vivo. Furthermore, high trafficking gene expression significantly correlated with increased risk of distant metastasis and reduced relapse-free and overall survival in breast cancer patients, suggesting that modulation of ER-Golgi trafficking plays an important role in metastatic progression.
Resistive switching offers a promising route to universal electronic memory, potentially replacing current technologies that are approaching their fundamental limits. In many cases switching ...originates from the reversible formation and dissolution of nanometre-scale conductive filaments, which constrain the motion of electrons, leading to the quantisation of device conductance into multiples of the fundamental unit of conductance, G0. Such quantum effects appear when the constriction diameter approaches the Fermi wavelength of the electron in the medium - typically several nanometres. Here we find that the conductance of silicon-rich silica (SiOx) resistive switches is quantised in half-integer multiples of G0. In contrast to other resistive switching systems this quantisation is intrinsic to SiOx, and is not due to drift of metallic ions. Half-integer quantisation is explained in terms of the filament structure and formation mechanism, which allows us to distinguish between systems that exhibit integer and half-integer quantisation.
We demonstrate the energy- and time-resolved detection of single-electron wave packets from a clock-controlled source transmitted through a high-energy quantum Hall edge channel. A quantum dot source ...is loaded with single electrons which are then emitted ~150 meV above the Fermi energy. The energy spectroscopy of emitted electrons indicates that at high magnetic field these electrons can be transported over several microns without inelastic electron-electron or electron-phonon scattering. Using a time-resolved spectroscopic technique, we deduce the wave packet size at picosecond resolution. We also show how this technique can be used to switch individual electrons into different electron waveguides (edge channels).
In this article, the American Cancer Society (ACS) provides estimates of new breast cancer cases and deaths in 2006 and describes trends in incidence, mortality, and survival for female breast cancer ...in the United States. These estimates are based on incidence data from the National Cancer Institute (NCI) and the North American Association of Central Cancer Registries, which includes state data from NCI and the National Program of Cancer Registries of the Centers for Disease Control and Prevention and mortality data from the National Center for Health Statistics for the most recent years available (1975 to 2002). This article also shows trends in screening mammography. Approximately 212,920 new cases of invasive breast cancer, 61,980 in situ cases, and 40,970 deaths are expected to occur among US women in 2006. As previously reported, breast cancer incidence rates increased rapidly among women of all races from 1980 to 1987, a period when there was increasing uptake of mammography by a growing proportion of US women, and then continued to increase, but at a much slower rate, from 1987 to 2002. Trends in incidence vary by age, race, socioeconomic status, and stage. The continuing increase in incidence (all stages combined) is limited to White women age 50 and older; recent trends are stable for African American women age 50 and older and White women under age 50 years and are decreasing for African American women under age 50 years. Although incidence rates (all races combined) are substantially higher for women age 50 and older (375.0 per 100,000 females) compared with women younger than 50 years (42.5 per 100,000 females), approximately 23% of breast cancers are diagnosed in women younger than 50 years because those women represent 73% of the female population. For women age 35 and younger, age‐specific incidence rates are slightly higher among African Americans compared with Whites but then cross over so that Whites have substantially higher incidence at all later ages. Among women of all races and ages, breast cancer mortality rates declined at an average rate of 2.3% per year between 1990 and 2002, a trend that reflects progress in both early detection and treatment. However, death rates in African American women remain 37% higher than in Whites, despite lower incidence rates. Although, in national surveys, approximately 70% of women age 40 years and older report having had a mammogram in the past 2 years, rates vary by race/ethnicity and are markedly lower among women with lower levels of education, without health insurance, and in recent immigrants. Furthermore, a recent study suggests that the true percentage of women having regular mammography is lower than reported in survey data. Encouraging patients age 40 years and older to have annual mammography and clinical breast exam is the single most important step that clinicians can take to reduce suffering and death from breast cancer. Clinicians should also ensure that patients at high risk of breast cancer are identified and offered appropriate referrals and treatment. Continued progress in the control of breast cancer will require sustained and increased efforts to provide high‐quality screening, diagnosis, and treatment to all segments of the population.
Emerging evidence indicates that arginine methylation promotes the stability of arginine-glycine-rich (RGG) motif-containing RNA-binding proteins (RBPs) and regulates gene expression. Here, we report ...that post-translational modification of FXR1 enhances the binding with mRNAs and is involved in cancer cell growth and proliferation. Independent point mutations in arginine residues of FXR1's nuclear export signal (R386 and R388) and RGG (R453, R455 and R459) domains prevent it from binding to RNAs that form G-quadruplex (G4) RNA structures. Disruption of G4-RNA structures by lithium chloride failed to bind with FXR1, indicating its preference for G4-RNA structure containing mRNAs. Furthermore, loss-of-function of PRMT5 inhibited FXR1 methylation both in vivo and in vitro, affecting FXR1 protein stability, inhibiting RNA-binding activity and cancer cell growth and proliferation. Finally, the enhanced crosslinking and immunoprecipitation (eCLIP) analyses reveal that FXR1 binds with the G4-enriched mRNA targets such as AHNAK, MAP1B, AHNAK2, HUWE1, DYNC1H1 and UBR4 and controls its mRNA expression in cancer cells. Our findings suggest that PRMT5-mediated FXR1 methylation is required for RNA/G4-RNA binding, which promotes gene expression in cancer cells. Thus, FXR1's structural characteristics and affinity for RNAs preferentially G4 regions provide new insights into the molecular mechanism of FXR1 in oral cancer cells.
A well-studied RNA-binding protein Hu Antigen-R (HuR), controls post-transcriptional gene regulation and undergoes stress-activated caspase-3 dependent cleavage in cancer cells. The cleavage products ...of HuR are known to promote cell death; however, the underlying molecular mechanisms facilitating caspase-3 activation and HuR cleavage remains unknown. Here, we show that HuR cleavage associated with active caspase-3 in oral cancer cells treated with ionizing radiation and chemotherapeutic drug, paclitaxel. We determined that oral cancer cells overexpressing cyclooxygenase-2 (COX-2) limited the cleavage of caspase-3 and HuR, which reduced the rate of cell death in paclitaxel resistant oral cancer cells. Specific inhibition of COX-2 by celecoxib, promoted apoptosis through activation of caspase-3 and cleavage of HuR in paclitaxel-resistant oral cancer cells, both in vitro and in vivo. In addition, oral cancer cells overexpressing cellular HuR increased the half-life of COX-2 mRNA, promoted COX-2 protein expression and exhibited enhanced tumor growth in vivo in comparison with cells expressing a cleavable form of HuR. Finally, our ribonucleoprotein immunoprecipitation and sequencing (RIP-seq) analyses of HuR in oral cancer cells treated with ionizing radiation (IR), determined that HuR cleavage product-1 (HuR-CP1) bound and promoted the expression of mRNAs encoding proteins involved in apoptosis. Our results indicated that, cellular non-cleavable HuR controls COX-2 mRNA expression and enzymatic activity. In addition, overexpressed COX-2 protein repressed the cleavage of caspase-3 and HuR to promote drug resistance and tumor growth. Altogether, our observations support the use of the COX-2 inhibitor celecoxib, in combination with paclitaxel, for the management of paclitaxel resistant oral cancer cells.
We investigated the effects of forest fragmentation on the disappearance of fruit-eating animals and the recruitment of animal-, wind-, and gravity-dispersed trees in 80-year-old forest patches in ...the East Usambara Mountains of Tanzania. We compared adult and juvenile trees in forest transects in a 3500-ha sub-montane forest with those in four forest fragments of 521, 30, 9, and 0.5 ha. Preliminary results show that recruitment of seedlings and juveniles of 31 animal-dispersed tree species was more than three times greater in continuous forest and large forest fragments (≥30 ha) than in small forest fragments (≤9 ha), whereas recruitment of eight wind- and gravity-dispersed trees of the forest interior was unaffected. Recruitment of 10 endemic, animal-dispersed tree species was 40 times lower in small fragments than in continuous forest or large fragments. Counts of diurnal primates and birds in all five sites indicated that frugivorous species have declined with decreasing fragment size. These results are consistent with the idea that loss of dispersal agents depresses tree recruitment in the course of forest fragmentation.
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