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Introns impact several vital aspects of eukaryotic organisms like proteomic plasticity, genomic stability, stress response and gene expression. A role for introns in the regulation of gene expression at the level of transcription has been known for more than thirty years. The molecular basis underlying the phenomenon, however, is still not entirely clear. An important clue came from studies performed in budding yeast that indicate that the presence of an intron within a gene results in formation of a multi-looped gene architecture. When looping is defective, these interactions are abolished, and there is no enhancement of transcription despite normal splicing. In this review, we highlight several potential mechanisms through which looping interactions may enhance transcription. The promoter-5′ splice site interaction can facilitate initiation of transcription, the terminator-3′ splice site interaction can enable efficient termination of transcription, while the promoter-terminator interaction can enhance promoter directionality and expedite reinitiation of transcription. Like yeast, mammalian genes also exhibit an intragenic interaction of the promoter with the gene body, especially exons. Such promoter-exon interactions may be responsible for splicing-dependent transcriptional regulation. Thus, the splicing-facilitated changes in gene architecture may play a critical role in regulation of transcription in yeast as well as in higher eukaryotes.Bacterial survival within a mammalian host is contingent upon sensing environmental perturbations and initiating an appropriate counter-response. To achieve this, sophisticated molecular machineries are used, where bacterial chaperone systems play key roles. The chaperones are a prerequisite for bacterial survival during normal physiological conditions as well as under stressful situations, e.g., infection or inflammation. Specific stress factors include, but are not limited to, high temperature, osmolarity, pH, reactive oxidative species, or bactericidal molecules. read more ClpB, a member of class 1 AAA+ proteins, is a key chaperone that via its disaggregase activity plays a crucial role for bacterial survival under various forms of stress, in particular heat shock. Recently, it has been reported that ClpB also regulates secretion of bacterial effector molecules related to type VI secretion systems. In this review, the roles of ClpB in stress responses and the mechanisms by which it promotes survival of pathogenic bacteria are discussed.In eukaryotic cells, three nuclear RNA polymerases (RNA pols) carry out the transcription from DNA to RNA, and they all seem to have evolved from a single enzyme present in the common ancestor with archaea. The multiplicity of eukaryotic RNA pols allows each one to remain specialized in the synthesis of a subset of transcripts, which are different in the function, length, cell abundance, diversity, and promoter organization of the corresponding genes. We hypothesize that this specialization of RNA pols has conditioned the evolution of the regulatory mechanisms used to transcribe each gene subset to cope with environmental changes. We herein present the example of the homeostatic regulation of transcript levels versus changes in cell volume. We propose that the diversity and instability of messenger RNAs, transcribed by RNA polymerase II, have conditioned the appearance of regulatory mechanisms based on different gene promoter strength and mRNA stability. However, for the regulation of ribosomal RNA levels, which are very stable and transcribed mainly by RNA polymerase I from only one promoter, different mechanisms act based on gene copy variation, and a much simpler regulation of the synthesis rate.Osteosarcoma serves as a prevalent bone cancer with a high metastasis and common drug resistance, resulting in poor prognosis and high mortality. Photodynamic therapy (PDT) is a patient-specific and non-invasive tumor therapy. Nanoparticles, like graphene oxide have been widely used in drug delivery and PDT. Ginsenoside Rg3 is a principal ginseng component and has presented significant anti-cancer activities. Here, we constructed the nanoparticles using GO linked with photosensitizer (PS) indocyanine green (ICG), folic acid, and polyethylene glycol (PEG), and loaded with Rg3 (PEG-GO-FA/ICG-Rg3). We aimed to explore the effect of PEG-GO-FA/ICG-Rg3 combined with PDT for the treatment of osteosarcoma. Significantly, we found that Rg3 repressed proliferation, invasion, and migration, and enhanced apoptosis and autophagy of osteosarcoma cells, while the PEG-GO-FA/ICG-Rg3 presented a higher activity, in which NIR laser co-treatment could remarkably increase the effect of PEG-GO-FA/ICG-Rg3. Meanwhile, stemness of osteosarcoma cell-derived cancer stem cells was inhibited by Rg3 and PEG-GO-FA/ICG-Rg3, and the combination of PEG-GO-FA/ICG-Rg3 with NIR laser further significantly attenuated this phenotype in the system. Moreover, NIR laser notably improved the inhibitor effect of PEG-GO-FA/ICG-Rg3 on the tumor growth of osteosarcoma cells in vivo. Consequently, we concluded that PEG-GO-FA/ICG-Rg3 improved PDT in inhibiting malignant progression and stemness of osteosarcoma cell. link2 Our finding provides a promising and practical therapeutic strategy for the combined treatment of osteosarcoma.In Colorectal cancer (CRC), adenomatous polyposis coli (APC) directly interacts with the Rho guanine nucleotide exchange factor 4 (Asef) and releases its GEF activity. Activated Asef promotes the aberrant migration and invasion of CRC cell through a CDC42-mediated pathway. Knockdown of either APC or Asef significantly decreases the migration of CRC cells. Therefore, disrupting the APC-Asef interaction is a promising strategy for the treatment of invasive CRC. With the growth of structural information, APC-Asef inhibitors have been designed, providing hope for CRC therapy. Here, we will review the APC-Asef interaction in cancer biology, the structural complex of APC-Asef, two generations of peptide inhibitors of APC-Asef, and small molecule inhibitors of APC-Asef, focusing on research articles over the past 30 years. We posit that these advances in the discovery of APC-Asef inhibitors establish the protein-protein interaction (PPI) as targetable and provide a framework for other PPI programs.Islet amyloid polypeptide (IAPP) is a proposed cause of the decreased beta-cell mass in patients with type-II diabetes. The molecular composition of the cell-membrane is important for regulating IAPP cytotoxicity and aggregation. Cholesterol is present at high concentrations in the pancreatic beta-cells, and in-vitro experiments have indicated that it affects the amyloid formation of IAPP either by direct interactions or by changing the properties of the membrane. In this study we apply atomistic, unbiased molecular dynamics simulations at a microsecond timescale to investigate the effect of cholesterol on membrane bound IAPP. Simulations were performed with various combinations of cholesterol, phosphatidylcholine (PC) and phosphatidylserine (PS) lipids. In all simulations, the helical structure of monomer IAPP was stabilized by the membrane. We found that cholesterol decreased the insertion depth of IAPP compared to pure phospholipid membranes, while PS lipids counteract the effect of cholesterol. The aggregation propensity has previously been proposed to correlate with the insertion depth of IAPP, which we found to decrease with the increased ordering of the lipids induced by cholesterol. Cholesterol is depleted in the vicinity of IAPP, and thus our results suggest that the effect of cholesterol is indirect.The inherent flexibility of intrinsically disordered proteins (IDPs) makes it difficult to interpret experimental data using structural models. On the other hand, molecular dynamics simulations of IDPs often suffer from force-field inaccuracies, and long simulation times or enhanced sampling methods are needed to obtain converged ensembles. Here, we apply metainference and Bayesian/Maximum Entropy reweighting approaches to integrate prior knowledge of the system with experimental data, while also dealing with various sources of errors and the inherent conformational heterogeneity of IDPs. We have measured new SAXS data on the protein α-synuclein, and integrate this with simulations performed using different force fields. We find that if the force field gives rise to ensembles that are much more compact than what is implied by the SAXS data it is difficult to recover a reasonable ensemble. On the other hand, we show that when the simulated ensemble is reasonable, we can obtain an ensemble that is consistent with the SAXS data, but also with NMR diffusion and paramagnetic relaxation enhancement data.

Furin is a calcium-dependent protease that processes various precursor proteins through diverse secretory pathways. The deregulation of FURIN correlated with the prognosis of patients in numerous diseases. link3 However, the role of FURIN in human pan-cancer is still largely unknown.

Multiple bioinformatic methods were employed to comprehensively analyze the correlation of FURIN expression with prognosis, mismatch repair (MMR), microsatellite instability (MSI), tumor mutational burden (TMB), DNA methylation, tumor immune infiltration, and common immune checkpoint inhibitors (ICIs) from the public database, and aim to evaluate the potential prognostic value of FURIN across cancers.

FURIN was aberrantly expressed and was strongly correlated with MMR, MSI, TMB, and DNA methylation in multiple types of cancer. Moreover, survival analysis across cancers revealed that FURIN expression was correlated with overall survival (OS) in four cancers, disease-specific survival (DSS) in five cancers, progression-free interval (PFI) in seven cancers, and disease-free interval (DFI) in two cancers. Also, FURIN expression was related to immune cell infiltration in 6 cancers and ImmuneScore/StromalScore in 10 cancers, respectively. In addition, FURIN expression also showed strong association between expression levels and immune checkpoint markers in three cancers.

FURIN can serve as a significant prognostic biomarker and correlate with tumor immunity in human pan-cancer.

FURIN can serve as a significant prognostic biomarker and correlate with tumor immunity in human pan-cancer.Gemcitabine (GEM) resistance remains a challenging clinical issue to overcome in chemotherapy against pancreatic cancer. We previously demonstrated that miR-210 derived from pancreatic cancer stem cells enhanced the GEM-resistant properties of pancreatic cancer cells, thus identifying miR-210 as an oncogenic miRNA. Herein, we report the existence of an upstream effector that acts as a competing endogenous RNA (ceRNA) to miR-210. Bioinformatic screening was performed to identify lncRNAs with a binding relationship to miR-210. Overexpression and interference vectors were constructed to demonstrate the effect of ceRNA activity in pancreatic cell behavior, both in vitro and in vivo. DLEU2L (deleted in lymphocytic leukemia 2-like), which is expressed at low levels in pancreatic cancer tissues, was shown to exhibit a binding relationship with miR-210-3p. Overexpression of DLEU2L and silencing of miR-210-3p suppressed the proliferation, migration, and invasion of pancreatic cancer cells while promoting apoptosis. These effects occurred via the inhibition of the Warburg effect (aerobic glycolysis) and AKT/mTOR signaling.