1,720,980 research outputs found
Autophagy roles in genome maintenance
No full textIn recent years, a considerable correlation has emerged between autophagy and genome integrity. A range of mechanisms appear to be involved where autophagy participates in preventing genomic instability, as well as in DNA damage response and cell fate decision. These initial findings have attracted particular attention in the context of malignancy; however, the crosstalk between autophagy and DNA damage response is just beginning to be explored and key questions remain that need to be addressed, to move this area of research forward and illuminate the overall consequence of targeting this process in human therapies. Here we present current knowledge on the complex crosstalk between autophagy and genome integrity and discuss its implications for cancer cell survival and response to therapy
Zinc-α2-glycoprotein hinders cell proliferation and reduces cdc2 expression
No full textZinc-α2-glycoprotein (Znα2gp) is widely distributed in body fluids and epithelia. Its expression in stratified epithelia increases with differentiation. We previously showed that Zn α2gp has ribonuclease activity, and that squamous tumor cells grown on a matrix of Znα2gp were growth-inhibited. Here we demonstrate, both by adding Znα2gp to the culture medium and, more unequivocally, by stably transfecting SiHa cells with Znα2gp cDNA, that the introduction of Znα2gp into SiHa tumor cells reduces proliferation. In response to Znα2gp, we find an accumulation of the cell population in G2/M by flow cytometry, paralleling the reduction of proliferation. In order to distinguish growth inhibition by cell cycle arrest from that produced by apoptosis or differentiation, we examine by RT-PCR how Znα2gp affects the expression of genes commonly used as markers of these properties. No changes are observed for PCNA, p53, c-myc, or bcl-2. Only cdc2 expression responds to Znα2gp, with a reduction of up to over a factor of two. Cdc2 is the only cyclin-dependent kinase regulating the G2/M transition without redundancy and is required as a rate-limiting step in the cell cycle. Its increased expression has been directly linked to increased proliferation and decreased differentiation of advanced tumors; conversely, its downregulation by Znα2gp might hinder tumor progression. © 2001 Wiley-Liss, Inc
Distinct regions of cyclinT1 are required for binding to CDK9 and for recruitment to the HIV-1 Tat/TAR complex
No full textTat-mediated activation of the HIV-1 promoter activity requires Tat-dependent recruitment of the cyclinT1/CDK9 complex (P-TEFb) to the transacting element (TAR) RNA. Tat interaction with the cyclinT1, the regulatory partner of CDK9, results in a specific recruitment of the heterodimer CycT1/CDK9 complex to TAR, whereby it promotes transcription elongation of the HIV-1 LTR-mediated transcription. Using the yeast two-hybrid protein interaction assay we analyzed the binding between cyclinT1 and CDK9. Moreover, using a modified three-hybrid yeast interaction system, we analyzed the recruitment of CycT1 to the Tat/TAR complex. The data presented here demonstrated that distinct domains of cyclinT1 interact with CDK9 and Tat/TAR in vivo. These findings will be instrumental for the designing of proper dominant-negative P-TEFb components capable to interfere with Tat function. © 2001 Wiley-Liss, Inc
MoNETA: MultiOmics Network Embedding for SubType Analysis
No full text: Cells are complex systems whose behavior emerges from a huge number of reactions taking place within and among different molecular districts. The availability of bulk and single-cell omics data fueled the creation of multi-omics systems biology models capturing the dynamics within and between omics layers. Powerful modeling strategies are needed to cope with the increased amount of data to be interrogated and the relative research questions. Here, we present MultiOmics Network Embedding for SubType Analysis (MoNETA) for fast and scalable identification of relevant multi-omics relationships between biological entities at the bulk and single-cells level. We apply MoNETA to show how glioma subtypes previously described naturally emerge with our approach. We also show how MoNETA can be used to identify cell types in five multi-omic single-cell datasets
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Constitutive and IL-6 induced nuclear factors that interact with the human C-reactive protein promoter
No full textTranscription of the human C-reactive protein (CRP) gene is induced by interleukin-6 (IL-6) during acute inflammation. Important information for inducible CRP expression is located within the 90 bases preceding the transcriptional start site. We show that the CRP promoter contains two adjacent binding sites (beta and alpha) that interact with at least two hepatocyte-specific nuclear proteins, H-APF-1 and H-APF-2. Point mutations that abolish or reduce binding drastically affect the level of CRP gene expression. Binding to beta is identical when extracts from uninduced or IL-6-induced Hep3B cells are used. On the contrary, both quantitative and qualitative changes in the alpha binding can be detected with extracts from uninduced cells or from cells treated with IL-6 or IL-6 + cycloheximide. A synthetic promoter based on the multimerization of the beta-binding domain, but not of the alpha-domain, is highly inducible when transfected in hepatoma cells. These results are discussed in relation to the structure of the promoter region of other acute phase inducible genes
The CDK9-associated Cyclins T1 and T2 exert opposite effects on HIV-1 Tat activity
No full textObjectives: To examine the functional interaction between HIV-1 Tat protein and the cyclin T1 and T2 proteins which, in association with cyclin dependent kinase (CDK)9, are the regulatory subunits of the TAK/P-TEFb cellular complex strictly required for Tat transactivation. Design: HIV-1 long terminal repeal (LTR) reporter plasmid was co-transfected into human and rodent cells with expression vectors encoding Tat and vectors encoding the cyclins T1, T2a and T2b, respectively. Methods: Tat-mediated transactivation of HIV-1 LTR-driven transcription was compared in the presence or absence or different cyclins T (T1, T2a and T2b), upon co-transfections into human and rodent cell lines. Protein interactions were analysed by in vitro binding assays. Results: It was found that Tat function in rodent cells is enhanced by co-expression of cyclin T1 but not cyclin T2. The N-terminal region (amino acids 1-290) of cyclin T1 is sufficient for this function and for binding to Tat and CDK9. Cyclin T2 binds to CDK9 but not to Tat. Moreover, enforced expression of cyclin T2 inhibits cyclin T1-mediated enhancement of Tat in rodent cells and it represses Tat activity in human cells. Conclusion: Efficient Tat transactivation in rodent cells occurs in the presence of human cyclin T1 but not in the presence of cyclin T2; overexpression of cyclin T2 inhibits Tat function in both rodent and human cells
Regulation of the human C-reactive protein gene, a major marker of inflammation and cancer
No full textHuman C-reactive protein (CRP) is the major acute phase reactant during inflammation. Regulation of CRP gene expression has been studied in two experimental systems: transgenic mice and human hepatoma cells. In the first system the human CRP gene flanked by approximately 10(4) bases of 5' and 3' sequences is expressed in a liver-specific and inducible manner. The chromatin configuration of the CRP transgene is characterized by the presence of constitutive and inducible liver-specific DNase I-hypersensitive sites. Inducible sites map precisely at the level of the CRP promoter region. In hepatoma cells we analysed the expression of the bacterial chloramphenicol acetyltransferase (CAT) gene driven by various segments of the CRP promoter. This latter approach has led to the identification of promoter elements responsive to interleukin-6 and of hepatocyte-specific nuclear proteins that interact with them
THE FCP1 PHOSPHATASE INTERACTS WITH RNA POLYMERASE II AND WITH MEP50 A COMPONENT OF THE METHYLOSOME COMPLEX INVOLVED IN THE ASSEMBLY OF SNRNP.
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