Lung cancer is the leading cause of cancer-related death worldwide. Aberrant splicing has been implicated in lung tumorigenesis. However, the functional links between splicing regulation and lung cancer are not well understood. Here we identify the RNA-binding protein QKI as a key regulator of alternative splicing in lung cancer. We show that QKI is frequently down-regulated in lung cancer, and its down-regulation is significantly associated with a poorer prognosis. QKI-5 inhibits the proliferation and transformation of lung cancer cells both in vitro and in vivo. Our results demonstrate that QKI-5 regulates the alternative splicing of NUMB via binding to two RNA elements in its pre-mRNA, which in turn suppresses cell proliferation and prevents the activation of the Notch signaling pathway. We further show that QKI-5 inhibits splicing by selectively competing with a core splicing factor SF1 for binding to the branchpoint sequence. Taken together, our data reveal QKI as a critical regulator of splicing in lung cancer and suggest a novel tumor suppression mechanism involving QKI-mediated regulation of the Notch signaling pathway.
BACKGROUND AND PURPOSE:Patients with mild cognitive impairment (MCI) are at risk for developing Alzheimer disease (AD). To diagnose AD at an early stage, one must develop highly specific and sensitive tools to identify it among at-risk subjects. The purpose of this study was to evaluate and compare the ability of fluorodeoxyglucose-positron-emission tomography (FDG-PET), single-photon emission tomography (SPECT), and structural MR imaging to predict conversion to AD in patients with MCI.
The human Y box-binding protein-1 (YB-1) is a deoxyribonucleic acid (DNA)/ribonucleic acid (RNA)-binding protein with pleiotropic functions. Besides its roles in the regulation of transcription and translation, several recent studies indicate that YB-1 is a spliceosome-associated protein and is involved in alternative splicing, but the underlying mechanism has remained elusive. Here, we define both CAUC and CACC as high-affinity binding motifs for YB-1 by systematic evolution of ligands by exponential enrichment (SELEX) and demonstrate that these newly defined motifs function as splicing enhancers. Interestingly, on the endogenous CD44 gene, YB-1 appears to mediate a network interaction to activate exon v5 inclusion via multiple CAUC motifs in both the alternative exon and its upstream polypyrimidine tract. We provide evidence that YB-1 activates splicing by facilitating the recruitment of U2AF65 to weak polypyrimidine tracts through direct protein–protein interactions. Together, these findings suggest a vital role of YB-1 in activating a subset of weak 3′ splice sites in mammalian cells.
The flexible organic amine cations on the interfaces of two-dimensional (2D) hybrid organic− inorganic perovskite nanosheets could form relaxed structures, which would lead to exotic optoelectronic properties but are hard to understand. Here, the unusual interfacial relaxation of nanosheets exfoliated from an o r t h o r h o m b i c 2 D l e a d h a l i d e p e r o v s k i t e , [(C 6 H 5 CH 2 NH 3 ) 2 ]PbCl 4 , is interrogated via ultrafast second-harmonic generation (SHG) spectroscopy. The in-plane SHG intensity anisotropy of these nanosheets is found to decrease with reducing layer thickness. Combined first-principles calculations and Monte Carlo simulations reveal that the induced second-order polarization arises primarily from the (C 6 H 5 CH 2 NH 3 ) + cations; and these organic amine cations form significantly reorganized conformations with decreasing nanosheet thickness due to weakened van der Waals interactions. Because the orientations of organic components at the interface determine their electric properties and specifically the dipolar susceptibility, the resulting structure leads to striking changes in the SHG properties.
Low-dimensional hybrid organic−inorganic perovskites (HOIPs) possess more localized electronic states and narrower conduction and valence bands to promote self-trapping of excitons and stronger exciton emission; therefore, they are widely used as building blocks for various applications in the fields of optoelectronics, photovoltaics, light-emitting diodes, luminescence, fluorescence, and so forth. Despite the past decades of intensive study, the discovered low-dimensional chiral HOIPs are rare as of the 1D chiral HOIP single crystals reported in 2003, as well as the low-dimensional chiral HOIP ferroelectrics are particularly scarce since the first chiral two-dimensional (2D) and/or one-dimensional (1D) HOIP ferroelectrics reported. Herein, two new low-dimensional HOIPs with the same conformational formula [R-MPA] 2 CdCl 4 (R-MPA + = (R)-(−)-1methyl-3-phenylpropylamine) were successfully synthetized by means of regulating the stoichiometric proportion of R-MPA and CdCl 2 in two ways of 1:1 (1) and 2:1 (2). By combining single-crystal X-ray diffraction, circular dichroism (CD) spectroscopy, differential scanning calorimetry, temperature-dependent dielectric constant, temperature-dependent second-harmonic generation (SHG) effect, polarization-dependent SHG response, and P−E hysteresis loop, we reveal that 1 is a 1D nonchiral molecular ferroelectric and 2 is the first zero-dimensional (0D) chiral ferroelectric with distinct CD signals; meanwhile, 2 exhibits increased properties of high-T c , large dielectric constant, SHG isotropy, and ferroelectricity than that of 1. These results not only shed light on the high tunability of the low-dimensional HOIP ferroelectrics but also open up an avenue to explore multifunctional chiral ferroelectrics.
The Y-box binding protein 1 (YB-1) is a member of the cold shock domain (CSD) protein family and is recognized as an oncogenic factor in several solid tumors. By binding to RNA, YB-1 participates in several steps of posttranscriptional regulation of gene expression, including mRNA splicing, stability, and translation; microRNA processing; and stress granule assembly. However, the mechanisms in YB-1–mediated regulation of RNAs are unclear. Previously, we used both systematic evolution of ligands by exponential enrichment (SELEX) and individual-nucleotide resolution UV cross-linking and immunoprecipitation coupled RNA-Seq (iCLIP-Seq) analyses, which defined the RNA-binding consensus sequence of YB-1 as CA(U/C)C. We also reported that through binding to its core motif CAUC in primary transcripts, YB-1 regulates the alternative splicing of a CD44 variable exon and the biogenesis of miR-29b-2 during both Drosha and Dicer steps. To elucidate the molecular basis of the YB-1–RNA interactions, we report high-resolution crystal structures of the YB-1 CSD in complex with different RNA oligos at 1.7 Å resolution. The structure revealed that CSD interacts with RNA mainly through π–π stacking interactions assembled by four highly conserved aromatic residues. Interestingly, YB-1 CSD forms a homodimer in solution, and we observed that two residues, Tyr-99 and Asp-105, at the dimer interface are important for YB-1 CSD dimerization. Substituting these two residues with Ala reduced CSD's RNA-binding activity and abrogated the splicing activation of YB-1 targets. The YB-1 CSD–RNA structures presented here at atomic resolution provide mechanistic insights into gene expression regulated by CSD-containing proteins.
Recent neuroimaging studies have shown that the cognitive and memory decline in patients with Alzheimer's disease (AD) is coupled with abnormal functions of focal brain regions and disrupted functional connectivity between distinct brain regions, as well as losses in small-world attributes. However, the causal interactions among the spatially isolated, but functionally related, resting state networks (RSNs) are still largely unexplored. In this study, we first identified eight RSNs by independent components analysis from resting state functional MRI data of 18 patients with AD and 18 age-matched healthy subjects. We then performed a multivariate Granger causality analysis (mGCA) to evaluate the effective connectivity among the RSNs. We found that patients with AD exhibited decreased causal interactions among the RSNs in both intensity and quantity relative to normal controls. Results from mGCA indicated that the causal interactions involving the default mode network and auditory network were weaker in patients with AD, whereas stronger causal connectivity emerged in relation to the memory network and executive control network. Our findings suggest that the default mode network plays a less important role in patients with AD. Increased causal connectivity of the memory network and self-referential network may elucidate the dysfunctional and compensatory processes in the brain networks of patients with AD. These preliminary findings may provide a new pathway towards the determination of the neurophysiological mechanisms of AD.
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