ABSTRACT
Hypoxia-inducible factor 1 (HIF1) is a master transcription factor that induces the transcription of genes involved in the metabolism and behavior of stem cells. HIF1-mediated adaptation to hypoxia is required to maintain the pluripotency and survival of stem cells under hypoxic conditions. HIF1 activity is well known to be tightly controlled by the alpha subunit of HIF1 (HIF1α). Understanding the regulatory mechanisms that control HIF1 activity in stem cells will provide novel insights into stem cell biology under hypoxia. Recent research has unraveled the mechanistic details of HIF1α regulating processes, suggesting new strategies for regulating stem cells. This review summarizes recent experimental studies on the role of several regulatory factors (including calcium, 2-oxoglutarate-dependent dioxygenase, microtubule network, importin, and coactivators) in regulating HIF1α activity in stem cells.
Subject(s)
Hypoxia , Biology , Calcium , Hypoxia-Inducible Factor 1 , Karyopherins , Metabolism , Microtubules , Stem Cells , Transcription FactorsABSTRACT
MicroRNAs (miRNAs) are conserved small non-coding RNAs that play an important role in the regulation of gene expression and participate in a variety of biological processes. The biogenesis of miRNAs is tightly controlled at multiple steps, such as transcription of miRNA genes, processing by Drosha and Dicer, and transportation of precursor miRNAs (pre-miRNAs) from the nucleus to the cytoplasm by exportin-5 (XPO5). Given the critical role of nuclear export of pre-miRNAs in miRNA biogenesis, any alterations of XPO5, resulting from either genetic mutation, epigenetic change, abnormal expression level or posttranslational modification, could affect miRNA expression and thus have profound effects on tumorigenesis. Importantly, XPO5 phosphorylation by ERK kinase and its cis/trans isomerization by the prolyl isomerase Pin1 impair XPO5's nucleo-to-cytoplasmic transport ability of pre-miRNAs, leading to downregulation of mature miRNAs in hepatocellular carcinoma. In this review, we focus on how XPO5 transports pre-miRNAs in the cells and summarize the dysregulation of XPO5 in human tumors.
Subject(s)
Humans , Carcinoma, Hepatocellular , Genetics , Metabolism , Cell Nucleus , Metabolism , Cytoplasm , Metabolism , Karyopherins , Chemistry , Metabolism , Physiology , Liver Neoplasms , Genetics , Metabolism , MicroRNAs , Chemistry , Metabolism , NIMA-Interacting Peptidylprolyl Isomerase , Neoplasms , Genetics , Metabolism , RNA Precursors , Chemistry , Metabolism , RNA TransportABSTRACT
Transportation between the cytoplasm and the nucleoplasm is critical for many physiological and pathophysiological processes including gene expression, signal transduction, and oncogenesis. So, the molecular mechanism for the transportation needs to be studied not only to understand cell physiological processes but also to develop new diagnostic and therapeutic targets. Recent progress in the research of the nuclear transportation (import and export) via nuclear pore complex and four important factors affecting nuclear transport (nucleoporins, Ran, karyopherins, and nuclear localization signals/nuclear export signals) will be discussed. Moreover, the clinical significance of nuclear transport and its application will be reviewed. This review will provide some critical insight for the molecular design of therapeutics which need to be targeted inside the nucleus.
Subject(s)
Active Transport, Cell Nucleus , Carcinogenesis , Cell Physiological Phenomena , Cytoplasm , Gene Expression , Karyopherins , Nuclear Localization Signals , Nuclear Pore , Nuclear Pore Complex Proteins , Signal Transduction , TransportationABSTRACT
Aging-dependent cellular behaviors toward extrinsic stress are characterized by the confined localization of certain molecules to either nuclear or perinuclear regions. Although most growth factors can activate downstream signaling in aging cells, they do not in fact have any impact on the cells because the signals cannot reach their genetic targets in the nucleus. For the same reason, varying apoptotic stress factors cannot stimulate the apoptotic pathway in senescent cells. Thus, the operation of a functional nuclear barrier in an aging-dependent manner has been investigated. To elucidate the mechanism for this process, the housekeeping transcription factor Sp1 was identified as a general regulator of nucleocytoplasmic trafficking (NCT) genes, including various nucleoporins, importins, exportins and Ran GTPase cycle-related genes. Interestingly, the posttranslational modification of Sp1 is readily influenced by extrinsic stress, including oxidative and metabolic stress. The decrease in SP1 O-GlcNAcylation under oxidative stress or during replicative senescence makes it susceptible to proteosomal degradation, resulting in defective NCT functions and leading to nuclear barrier formation. The operation of the nuclear barrier in aging provides a fundamental mechanism for cellular protection against stress and promotes survival at the expense of growth via stress-sensitive transcriptional control.
Subject(s)
Aging , Cellular Senescence , GTP Phosphohydrolases , Household Work , Intercellular Signaling Peptides and Proteins , Karyopherins , Nuclear Pore Complex Proteins , Oxidative Stress , Protein Processing, Post-Translational , Stress, Physiological , Transcription FactorsABSTRACT
The HIV-1 Rev protein facilitates nuclear export of unspliced and singly spliced viral transcripts containing RRE RNA through the CRM1 export pathway. Inhibition of Rev-mediated RNA nuclear export can arrest HIV-1 transcriptional process, which clearly, reveals a target for anti-HIV drug development. In this work, a cell-based assay has been established for screening anti-HIV compounds targeting the Rev-mediated RNA nuclear export. This assay utilized a codon-optimized green fluorescent protein (GFP) as reporter gene, which expression is in a Rev-dependent manner. Any compound that inhibits the Rev-mediated RNA nuclear export is identified by reducing emission of GFP. The Z' score of this model is 0.8220. Three thousands compounds were screened and the positive rate was 9.3% with a cutoff at 50% inhibition. IMB7C7, one of the positive compounds, efficiently inhibits viral production from HIV-1 infected cells.
Subject(s)
Humans , Active Transport, Cell Nucleus , Anti-HIV Agents , Pharmacology , Cell Nucleus , Metabolism , Codon , Fatty Acids, Unsaturated , Pharmacology , Genes, Reporter , Green Fluorescent Proteins , Genetics , Metabolism , HEK293 Cells , HIV-1 , Genetics , High-Throughput Screening Assays , Karyopherins , Genetics , Metabolism , RNA, Viral , Receptors, Cytoplasmic and Nuclear , Genetics , Metabolism , Transfection , Virus Replication , rev Gene Products, Human Immunodeficiency Virus , Genetics , MetabolismABSTRACT
HIV-1 Rev is an indispensable regulatory factor of the virion protein expression. The interaction between Rev and RRE RNA accelerates the nuclear export of viral mRNA. The unspliced and singly spliced mRNA will be degraded in the absence of Rev, resulting in the interception of HIV-1 replication at the same time. The pivotal role that Rev plays in HIV-1 replication as a trans-acting factor makes it a new target in the research of AIDS drugs. In this review, the function of Rev, Rev-RRE interaction, as well as their related inhibitors are reported.
Subject(s)
Active Transport, Cell Nucleus , Amino Acid Sequence , Anti-HIV Agents , Chemistry , Pharmacology , Cell Nucleus , Metabolism , Fatty Acids, Unsaturated , Chemistry , Pharmacology , Framycetin , Chemistry , Pharmacology , HIV-1 , Genetics , Metabolism , Physiology , Karyopherins , Metabolism , RNA, Messenger , Genetics , RNA, Viral , Genetics , Receptors, Cytoplasmic and Nuclear , Metabolism , Transcription, Genetic , Virus Replication , rev Gene Products, Human Immunodeficiency Virus , MetabolismABSTRACT
<p><b>OBJECTIVE</b>To investigate the expression and relationship of p27(kip1) and its related molecules Jab1 and CRM1 during proliferation of lymphoma cells U937.</p><p><b>METHODS</b>U937 cells were treated with serum starvation and release, and the effects of these treatments on the cell growth was tested with cell number counting. The expression and localization of p27(kip1), Jab1 and CRM1 in U937 cells were detected by Western blot, double immunolabelling and laser scanning confocal microscopy.</p><p><b>RESULTS</b>The growth of U937 cells was blocked by serum starvation. The total protein of p27(kip1) was increased while Ser10-phosphorylated p27(kip1) -related molecules Jab1 and CRM1 were decreased. Meanwhile, the location of p27(kip1) was changed from cytoplasm into nuclei. After serum release, the location of p27(kip1) expression reappeared in the cytoplasm again.</p><p><b>CONCLUSION</b>During the proliferation process of lymphoma U937 cells, Jab1 and CRM1 may influence the location and expression of p27kip1, and may participate in regulation of growth of NHL cells.</p>
Subject(s)
Humans , COP9 Signalosome Complex , Cell Culture Techniques , Cell Nucleus , Metabolism , Cell Proliferation , Culture Media, Serum-Free , Pharmacology , Cyclin-Dependent Kinase Inhibitor p27 , Metabolism , Cytoplasm , Metabolism , Intracellular Signaling Peptides and Proteins , Metabolism , Karyopherins , Metabolism , Peptide Hydrolases , Metabolism , Receptors, Cytoplasmic and Nuclear , Metabolism , U937 CellsABSTRACT
Las células eucarióticas han desarrollado diferentes mecanismos para la exportación de diferentes ARNs celulares codificantes (ARNm) y no-codificantes (rARN, tARN, snARN), desde el núcleo hacia el citoplasma, donde participan activamente en la producción de proteínas. Las diferentes clases de ARNs son exportadas a través del complejo del poro nuclear (CPN) e intervienen proteínas de la familia de las carioferinas, que pueden ser dependientes o independientes de la proteína Ran. La exportación es un mecanismo específico, coordinado y altamente regulado a través de interacciones proteína-proteína o proteína-ARN. Sin embargo, muchos virus tales como el virus de la inmunodeficiencia humana tipo 1 (VIH-1), han desarrollado un mecanismo de exportación selectivo del ARNm viral. Para tal propósito, el genoma del virus codifica por la proteína Rev, responsable de regular la expresión del genoma viral y de la exportación de los diferentes transcritos virales, interactuando en cis con un ARN altamente estructurado presente en los transcritos virales semiprocesados y sin procesar, en asocio con las proteínas celulares implicadas en la exportación. Con esta revisión se pretende hacer un análisis de los diferentes eventos que ocurren en este proceso, en especial las interacciones proteína-proteína o proteína-ácidos nucleicos. De igual manera, se discutirá la importancia de la proteína Rev del VIH-1, en la exportación de los transcritos virales sin procesar y sus interacciones con las proteínas celulares para llevar a cabo su misión