SUMMARY It has been suspected that cell cycle progression might be functionally coupled with RNA processing. However, little is known about the role of the precise splicing control in cell cycle progression. Here, we report that SON, a large Ser/Arg (SR)-related protein, is a splicing co-factor contributing to efficient splicing of cell cycle regulators. Down-regulation of SON leads to severe impairment of spindle pole separation, microtubule dynamics, and genome integrity. These molecular defects result from inadequate RNA splicing of a specific set of cell cycle-related genes that possess weak splice sites. Furthermore, we show that SON facilitates the interaction of SR proteins with RNA polymerase II and other key spliceosome components, suggesting its function in efficient co-transcriptional RNA processing. These results reveal a mechanism for controlling cell cycle progression through SON-dependent constitutive splicing at suboptimal splice sites, with strong implications for its role in cancer and other human diseases.
AML1-ETO is generated from t(8;21)(q22;q22), which is a common form of chromosomal translocation associated with development of acute myeloid leukemia (AML). Although full-length AML1-ETO alone fails to promote leukemia because of its detrimental effects on cell proliferation, an alternatively spliced isoform, AML1-ETO9a, without its C-terminal NHR3/NHR4 domains, strongly induces leukemia. However, full-length AML1-ETO is a major form of fusion product in many t(8;21) AML patients, suggesting additional molecular mechanisms of t(8;21)-related leukemogenesis. Here, we report that disruption of the zinc-chelating structure in the NHR4 domain of AML1-ETO by replacing only one critical amino acid leads to rapid onset of leukemia, demonstrating that the NHR4 domain with the intact structure generates inhibitory effects on leukemogenesis. C hromosomal translocation is one of the most common genetic abnormalities in acute myeloid leukemia (AML) (1). AML1-ETO is a fusion protein transcription factor generated from t(8;21)(q22;q22). This translocation is identified in Ͼ10% of all cases and up to 40% of the French-American-British M2 subtype of AML (2-5). However, expression of AML1-ETO by itself fails to cause leukemia (6-11), which suggests the requirement of ''additional hits'' for AML1-ETO-positive cells to become leukemogenic.Previously, our group reported that the C-terminally truncated form of AML1-ETO (AML1-ETOtr) is strongly leukemogenic (12). Interestingly, a short form of AML1-ETO, AML1-ETO9a, which is produced by alternative splicing, was identified in t(8;21) leukemia patient samples, and expression of AML1-ETO9a induced rapid leukemia development in mice (13). AML1-ETOtr and AML1-ETO9a encode 556 and 575 aa (a.a.), respectively, and both lack the NHR3 and NHR4 regions. These results suggest that the N-terminal portion of ETO (NHR1 and NHR2) fused with AML1, is sufficient to cause leukemia. In addition, the C-terminal domains of AML1-ETO (NHR3 and NHR4) may actually play a role in suppressing disease development.In this report, we demonstrate that the zinc (Zn)-chelating structure of the NHR4 is responsible for generating inhibitory effects on leukemia development, and that this region interacts with SON, a potential DNA/RNA-binding protein, to cause growth arrest in AML1-ETO-expressing cells. Furthermore, we demonstrate a crucial role of SON in cell proliferation, and abnormal localization of SON in AML1-ETO-expressing leukemia patient samples.
Promotion of osteoclast apoptosis is one therapeutic approach to osteoporosis. Calmodulin, the major intracellular Ca 2؉
BackgroundTo compare the outcomes of gastric, colon, lung, and breast cancer patients with and without rheumatic diseases (RD).MethodsThis retrospective study compared the cancer survival rates of a cohort of 122 cancer patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), dermatomyositis/polymyositis (DM/PM), or systemic sclerosis with that of a cohort of 366 age-, sex-, and, cancer type-matched patients without RD who received medical care from 2000 to 2014. Staging, comorbidities, and functional status were ascertained. Survival was compared using the Kaplan-Meier method. Relative risk of death was estimated as a hazard ratio (HR) using Cox regression analysis.ResultsThe mean age of the RD patients at the time of cancer diagnosis was 58.7 ± 11.5 years. The overall survival rate of gastric cancer patients did not differ between the cohorts. The survival of lung or breast cancer was worse in patients with RA or DM/PM than in those without RD (all, p < 0.05). After adjusting for cancer stage, comorbidity index, performance status and age at the time of cancer diagnosis (as well as interstitial lung disease for lung cancer group), the mortality rate among lung cancer patients with RA was significantly higher (HR, 1.81; 95 % CI, 1.03–3.18) than that of lung cancer patients without RD, whereas SSc was associated with decreased mortality of lung cancer (HR, 0.16; 95 % CI, 0.04–0.58). DM/PM were associated with increased mortality of breast cancer patients (HR, 297.39; 95 % CI, 4.24–20842.33).ConclusionsRA and DM/PM seemed to be associated with a higher mortality in patients with lung or breast cancers, whereas SSc seemed to be associated with decreased mortality in patients with lung cancer. It is warranted to explore the survival effect of tailored cancer treatments according to specific RD.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2444-5) contains supplementary material, which is available to authorized users.
Many pathogenic bacteria, including Escherichia coli O157:H7, can control gene expression in a cell density-dependent manner by producing small signaling molecules (autoinducers) in a process known as quorum sensing. In this study, the effects of the autoinducer-2-like activity on the expression of proteins, including virulence factors, in E. coli O157:H7 were characterized by proteomic analysis. Compared with the control, E. coli O157:H7 strains in the presence of autoinducer-2-like activity exhibited elevated virulence by more rapidly forming cell aggregates on epithelial cells and rapidly killing the nematode Caenorhabditis elegans, the surrogate host. Two-dimensional gel electrophoresis revealed 18 proteins that were upregulated by autoinducer-2-like activity and 4 proteins that were down-regulated. These proteins were further characterized by matrix-assisted laser desorption-ionization time-of-flight mass spectrometry and are involved in the metabolic process, adaptation and protection, cell motility, secretion, envelope biogenesis, and protein translation. These results indicate that the newly identified proteins are associated with the control of virulence in E. coli O157:H7 and that these proteins can be potential targets for the development of antibiotics and other antimicrobial agents.
Trimetazidine appeared to improve clinical outcomes in AMI patients by significantly reducing all-cause mortality and MACE over 12 months.
BackgroundTo examine the structural and oxidative properties of lipoproteins from patients with systemic lupus erythematosus (SLE).MethodsThe lipid profiles of 35 SLE patients and 15 healthy controls (HCs) were compared. Oxidation status, susceptibility to oxidation, and structural integrity of low-density lipoprotein (LDL) were determined by measuring malondialdehyde (MDA), de novo formation of conjugated dienes in the presence of CuSO4, and mobility on gel electrophoresis, respectively. In vitro foam cell formation and the oxidative potential in zebrafish embryos were examined.ResultsLDL levels in SLE patients and HCs were similar (p = 0.277). LDL from SLE patients was more fragmented than that from HCs. In addition, LDL from SLE patients was more oxidized than LDL from HCs (p < 0.001) and more susceptible to de novo oxidation (p < 0.001) in vitro. THP-1 cells engulfed more LDL from SLE patients than LDL from HCs (p < 0.001). LDL from SLE patients, which was injected into zebrafish embryos, induced a higher degree of oxidation and a higher mortality than LDL from HCs (both p < 0.001). The survival of embryos treated with oxidized LDL was significantly better in the presence of HDL3 from HCs than that from SLE patients (all p < 0.001).ConclusionsLipoproteins from SLE patients exhibited greater oxidative potential, which might contribute to accelerated atherosclerosis in SLE.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-016-1204-x) contains supplementary material, which is available to authorized users.
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