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      HIF-1 and SKN-1 Coordinate the Transcriptional Response to Hydrogen Sulfide in Caenorhabditis elegans

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      1 , 2 , * , 2 , 3 , 2 , *

      PLoS ONE

      Public Library of Science

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          Abstract

          Hydrogen sulfide (H 2S) has dramatic physiological effects on animals that are associated with improved survival. C. elegans grown in H 2S are long-lived and thermotolerant. To identify mechanisms by which adaptation to H 2S effects physiological functions, we have measured transcriptional responses to H 2S exposure. Using microarray analysis we observe rapid changes in the abundance of specific mRNAs. The number and magnitude of transcriptional changes increased with the duration of H 2S exposure. Functional annotation suggests that genes associated with protein homeostasis are upregulated upon prolonged exposure to H 2S. Previous work has shown that the hypoxia-inducible transcription factor, HIF-1, is required for survival in H 2S. In fact, we show that hif-1 is required for most, if not all, early transcriptional changes in H 2S. Moreover, our data demonstrate that SKN-1, the C. elegans homologue of NRF2, also contributes to H 2S-dependent changes in transcription. We show that these results are functionally important, as skn-1 is essential to survive exposure to H 2S. Our results suggest a model in which HIF-1 and SKN-1 coordinate a broad transcriptional response to H 2S that culminates in a global reorganization of protein homeostasis networks.

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          Most cited references 28

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          DAVID: Database for Annotation, Visualization, and Integrated Discovery.

          Functional annotation of differentially expressed genes is a necessary and critical step in the analysis of microarray data. The distributed nature of biological knowledge frequently requires researchers to navigate through numerous web-accessible databases gathering information one gene at a time. A more judicious approach is to provide query-based access to an integrated database that disseminates biologically rich information across large datasets and displays graphic summaries of functional information. Database for Annotation, Visualization, and Integrated Discovery (DAVID; http://www.david.niaid.nih.gov) addresses this need via four web-based analysis modules: 1) Annotation Tool - rapidly appends descriptive data from several public databases to lists of genes; 2) GoCharts - assigns genes to Gene Ontology functional categories based on user selected classifications and term specificity level; 3) KeggCharts - assigns genes to KEGG metabolic processes and enables users to view genes in the context of biochemical pathway maps; and 4) DomainCharts - groups genes according to PFAM conserved protein domains. Analysis results and graphical displays remain dynamically linked to primary data and external data repositories, thereby furnishing in-depth as well as broad-based data coverage. The functionality provided by DAVID accelerates the analysis of genome-scale datasets by facilitating the transition from data collection to biological meaning.
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            HIF-1: mediator of physiological and pathophysiological responses to hypoxia.

            All organisms can sense O(2) concentration and respond to hypoxia with adaptive changes in gene expression. The large body size of mammals necessitates the development of multiple complex physiological systems to ensure adequate O(2) delivery to all cells under normal conditions. The transcriptional regulator hypoxia-inducible factor 1 (HIF-1) is an essential mediator of O(2) homeostasis. HIF-1 is required for the establishment of key physiological systems during development and their subsequent utilization in fetal and postnatal life. HIF-1 also appears to play a key role in the pathophysiology of cancer, cardiovascular disease, and chronic lung disease, which represent the major causes of mortality among industrialized societies. Genetic or pharmacological modulation of HIF-1 activity in vivo may represent a novel therapeutic approach to these disorders.
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              SKP1 connects cell cycle regulators to the ubiquitin proteolysis machinery through a novel motif, the F-box.

              We have identified the yeast and human homologs of the SKP1 gene as a suppressor of cdc4 mutants and as a cyclin F-binding protein. Skp1p indirectly binds cyclin A/Cdk2 through Skp2p, and directly binds Skp2p, cyclin F, and Cdc4p through a novel structural motif called the F-box. SKP1 is required for ubiquitin-mediated proteolysis of Cin2p, Clb5p, and the Cdk inhibitor Sic1p, and provides a link between these molecules and the proteolysis machinery. A large number of proteins contain the F-box motif and are thereby implicated in the ubiquitin pathway. Different skp1 mutants arrest cells in either G1 or G2, suggesting a connection between regulation of proteolysis in different stages of the cycle.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2011
                29 September 2011
                : 6
                : 9
                Affiliations
                [1 ]Department of Biochemistry, University of Washington School of Medicine, Seattle, Washington, United States of America
                [2 ]Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
                [3 ]University of Washington Molecular and Cellular Biology Graduate Program, Seattle, Washington, United States of America
                University of Pennslyvania, United States of America
                Author notes

                Conceived and designed the experiments: DLM MWB MBR. Performed the experiments: DLM MWB. Analyzed the data: DLM MWB. Wrote the paper: DLM.

                Article
                PONE-D-11-09953
                10.1371/journal.pone.0025476
                3183046
                21980473
                Miller et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Page count
                Pages: 10
                Categories
                Research Article
                Biology
                Anatomy and Physiology
                Physiological Processes
                Aging
                Homeostasis
                Cell Physiology
                Biochemistry
                Metabolism
                Oxygen Metabolism
                Genetics
                Gene Expression
                Molecular Genetics
                Model Organisms
                Animal Models
                Caenorhabditis Elegans
                Molecular Cell Biology
                Cellular Stress Responses

                Uncategorized

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