3 research outputs found

    PTEN Physically Interacts with and Regulates E2F1-mediated Transcription in Lung Cancer

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    <p>PTEN phosphorylation at its C-terminal (C-tail) serine/threonine cluster negatively regulates its tumor suppressor function. However, the consequence of such inhibition and its downstream effects in driving lung cancer remain unexplored. Herein, we ascertain the molecular mechanisms by which phosphorylation compromises PTEN function, contributing to lung cancer. Replacement of the serine/threonine residues with alanine generated PTEN-4A, a phosphorylation-deficient PTEN mutant, which suppressed lung cancer cell proliferation and migration. PTEN-4A preferentially localized to the nucleus where it suppressed E2F1-mediated transcription of cell cycle genes. PTEN-4A physically interacted with the transcription factor E2F1 and associated with chromatin at gene promoters with E2F1 DNA-binding sites, a likely mechanism for its transcriptional suppression function. Deletion analysis revealed that the C2 domain of PTEN was indispensable for suppression of E2F1-mediated transcription. Further, we uncovered cancer-associated C2 domain mutant proteins that had lost their ability to suppress E2F1-mediated transcription, supporting the concept that these mutations are oncogenic in patients. Consistent with these findings, we observed increased PTEN phosphorylation and reduced nuclear PTEN levels in lung cancer patient samples establishing phosphorylation as a bona fide inactivation mechanism for PTEN in lung cancer. Thus, use of small molecule inhibitors that hinder PTEN phosphorylation is a plausible approach to activate PTEN function in the treatment of lung cancer.</p> <p>AbbreviationsAKT</p><p>V-Akt Murine Thymoma Viral Oncogene</p>CA<p>Cancer adjacent</p>CDK1<p>Cyclin dependent kinase 1</p>CENPC-C<p>Centromere Protein C</p>ChIP<p>Chromatin Immunoprecipitation</p>co-IP<p>Co-immunoprecipitation</p>COSMIC<p>Catalog of Somatic Mutations In Cancer</p>CREB<p>cAMP Responsive Element Binding Protein</p>C-tail<p>Carboxy terminal tail</p>E2F1<p>E2F Transcription Factor 1</p>ECIS<p>Electric Cell-substrate Impedance Sensing</p>EGFR<p>Epidermal Growth Factor Receptor</p>GSI<p>Gamma Secretase Inhibitor</p>HDAC1<p>Histone Deacetylase 1</p>HP1<p>Heterochromatin protein 1</p>KAP1/TRIM28<p>KRAB-Associated Protein 1/Tripartite Motif Containing 28</p>MAF1<p>Repressor of RNA polymerase III transcription MAF1 homolog</p>MCM2<p>Minichromosome Maintenance Complex Component 2</p>miRNA<p>micro RNA</p>MTF1<p>Metal-Regulatory Transcription Factor 1</p>PARP<p>Poly(ADP-Ribose) Polymerase</p>PD-1<p>Programmed Cell Death 1</p>PD-L1<p>Programmed Cell Death 1 Ligand 1</p>PI3K<p>Phosphatidylinositol-4,5-Bisphosphate 3-Kinase</p>PLK<p>Polo-like Kinase</p>pPTEN<p>Phosphorylated PTEN</p>PTEN<p>Phosphatase and Tensin Homolog deleted on chromosome ten</p>PTM<p>Post Translational Modification</p>Rad51<p>RAD51 Recombinase</p>Rad52<p>RAD52 Recombinase</p>RPA1<p>Replication protein A</p>SILAC<p>Stable Isotope Labeling with Amino Acids in Cell Culture</p>SRF<p>Serum Response Factor</p>TKI<p>Tyrosine Kinase inhbitors</p>TMA<p>Tissue Microarray</p>TOP2A<p>DNA Topoisomerase 2A</p><p></p> <p>V-Akt Murine Thymoma Viral Oncogene</p> <p>Cancer adjacent</p> <p>Cyclin dependent kinase 1</p> <p>Centromere Protein C</p> <p>Chromatin Immunoprecipitation</p> <p>Co-immunoprecipitation</p> <p>Catalog of Somatic Mutations In Cancer</p> <p>cAMP Responsive Element Binding Protein</p> <p>Carboxy terminal tail</p> <p>E2F Transcription Factor 1</p> <p>Electric Cell-substrate Impedance Sensing</p> <p>Epidermal Growth Factor Receptor</p> <p>Gamma Secretase Inhibitor</p> <p>Histone Deacetylase 1</p> <p>Heterochromatin protein 1</p> <p>KRAB-Associated Protein 1/Tripartite Motif Containing 28</p> <p>Repressor of RNA polymerase III transcription MAF1 homolog</p> <p>Minichromosome Maintenance Complex Component 2</p> <p>micro RNA</p> <p>Metal-Regulatory Transcription Factor 1</p> <p>Poly(ADP-Ribose) Polymerase</p> <p>Programmed Cell Death 1</p> <p>Programmed Cell Death 1 Ligand 1</p> <p>Phosphatidylinositol-4,5-Bisphosphate 3-Kinase</p> <p>Polo-like Kinase</p> <p>Phosphorylated PTEN</p> <p>Phosphatase and Tensin Homolog deleted on chromosome ten</p> <p>Post Translational Modification</p> <p>RAD51 Recombinase</p> <p>RAD52 Recombinase</p> <p>Replication protein A</p> <p>Stable Isotope Labeling with Amino Acids in Cell Culture</p> <p>Serum Response Factor</p> <p>Tyrosine Kinase inhbitors</p> <p>Tissue Microarray</p> <p>DNA Topoisomerase 2A</p

    DataSheet_1_Gut microbiota and fecal metabolic signatures in rat models of disuse-induced osteoporosis.docx

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    BackgroundAssessing the correlation between gut microbiota (GM) and bone homeostasis has increasingly attracted research interest. Meanwhile, GM dysbiosis has been found to be associated with abnormal bone metabolism. However, the function of GM in disuse-induced osteoporosis (DIO) remains poorly understood. In our research, we evaluated the characteristics of GM and fecal metabolomics to explore their potential correlations with DIO pathogenesis.MethodsDIO rat models and controls (CON) underwent micro-CT, histological analyses, and three-point bending tests; subsequently, bone microstructures and strength were observed. ELISAs were applied for the measurement of the biochemical markers of bone turnover while GM abundance was observed using 16S rDNA sequencing. Metabolomic analyses were used to analyze alterations fecal metabolites. The potential correlations between GM, metabolites, and bone loss were then assessed.ResultsIn the DIO group, the abundance of GM was significantly altered compared to that in the CON group. Moreover, DIO significantly altered fecal metabolites. More specifically, an abnormally active pathway associated with bile acid metabolism, as well as differential bacterial genera related to bone/tissue volume (BV/TV), were identified. Lithocholic acid, which is the main secondary bile acid produced by intestinal bacteria, was then found to have a relationship with multiple differential bacterial genera. Alterations in the intestinal flora and metabolites in feces, therefore, may be responsible for DIO-induced bone loss.ConclusionsThe results indicated that changes in the abundance of GM abundance and fecal metabolites were correlated with DIO-induced bone loss, which might provide new insights into the DIO pathogenesis. The detailed regulatory role of GM and metabolites in DIO-induced bone loss needs to be explored further.</p

    Table1_Population structure, dispersion patterns and genetic diversity of two major invasive and commensal zoonotic disease hosts (Rattus norvegicus and Rattus tanezumi) from the southeastern coast of China.XLSX

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    Background: The invasive brownrat (Rattus norvegicus) and the Oriental rats (Rattus tanezumi) are common commensal murid that are important hosts for rodent-borne diseases in southeast Asia. Understanding their population structure and genetic diversity is essential to uncover their invasion biology and distribution dynamics that are essential for controlling rodent-borne diseases.Methods: TA total of 103 R. norvegicus and 85 R. tanezumi were collected from 13 to 9 coastal areas of six provincial monitoring sentinel sites, respectivelyto assess patterns in their microsatellite loci and their mitochondrial coxl gene region.Results: Eleven sampled populations of R. norvegicus were divided into two major clusters by region. The observed heterozygosity values of all regional populations were smaller than expected genetic diversity heterozygosity values and deviated from Hardy-Weinberg equilibrium Nine sample populations of R. tanezumi were divided into three clusters; two that included sample from Hainan and Fujian provinces, and one that included samples from the other provinces and cities. The genetic diversity of R. tanezumi was highest in samples from Jiangsu and Guangdong provinces.Conclusion: The data in this paper confirm the two invasive rodent species from the southeastern coastal region of China may have relied on maritime transport to spread from the southern region of China to the Yangtze River basin. R. tanezumi may then hanve migrated unidirectionally, along the southeastern provinces of China towards the north, while R. norvegicus spread in a complex and multidirectional manner in Hainan, Fujian, Zhejiang and Jiangsu Provinces of the country.</p
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