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      Acute Vhl Gene Inactivation Induces Cardiac HIF-Dependent Erythropoietin Gene Expression

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          Abstract

          Von Hippel Lindau ( Vhl) gene inactivation results in embryonic lethality. The consequences of its inactivation in adult mice, and of the ensuing activation of the hypoxia-inducible factors (HIFs), have been explored mainly in a tissue-specific manner. This mid-gestation lethality can be also circumvented by using a floxed Vhl allele in combination with an ubiquous tamoxifen-inducible recombinase Cre-ER T2. Here, we characterize a widespread reduction in Vhl gene expression in Vhl floxed-UBC-Cre-ER T2 adult mice after dietary tamoxifen administration, a convenient route of administration that has yet to be fully characterized for global gene inactivation. Vhl gene inactivation rapidly resulted in a marked splenomegaly and skin erythema, accompanied by renal and hepatic induction of the erythropoietin ( Epo) gene, indicative of the in vivo activation of the oxygen sensing HIF pathway. We show that acute Vhl gene inactivation also induced Epo gene expression in the heart, revealing cardiac tissue to be an extra-renal source of EPO. Indeed, primary cardiomyocytes and HL-1 cardiac cells both induce Epo gene expression when exposed to low O 2 tension in a HIF-dependent manner. Thus, as well as demonstrating the potential of dietary tamoxifen administration for gene inactivation studies in UBC-Cre-ER T2 mouse lines, this data provides evidence of a cardiac oxygen-sensing VHL/HIF/EPO pathway in adult mice.

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          Most cited references 42

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          HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing.

           M Ivan,  Theresa Kim,  A Salic (2001)
          HIF (hypoxia-inducible factor) is a transcription factor that plays a pivotal role in cellular adaptation to changes in oxygen availability. In the presence of oxygen, HIF is targeted for destruction by an E3 ubiquitin ligase containing the von Hippel-Lindau tumor suppressor protein (pVHL). We found that human pVHL binds to a short HIF-derived peptide when a conserved proline residue at the core of this peptide is hydroxylated. Because proline hydroxylation requires molecular oxygen and Fe(2+), this protein modification may play a key role in mammalian oxygen sensing.
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            Regulation of Cre recombinase activity by mutated estrogen receptor ligand-binding domains.

            Ligand-dependent chimeric Cre recombinases are powerful tools to induce specific DNA rearrangements in cultured cells and in mice. We report here the construction and characterization of a series of chimeric recombinases, each consisting of Cre fused to a mutated human oestrogen receptor (ER) ligand-binding domain (LBD). Two new ligand-dependent recombinases which contain either the G400V/M543A/L544A or the G400V/L539A/L540A triple mutation of the human ER LBD are efficiently induced by the synthetic ER antagonists 4-hydroxytamoxifen (OHT) and ICI 182,780 (ICI), respectively, but are insensitive to 17 beta-oestradiol (E2). Both chimeric recombinases should be useful for efficient spatio-temporally controlled site-directed somatic mutagenesis.
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              Deletion of the developmentally essential gene ATR in adult mice leads to age-related phenotypes and stem cell loss.

              Developmental abnormalities, cancer, and premature aging each have been linked to defects in the DNA damage response (DDR). Mutations in the ATR checkpoint regulator cause developmental defects in mice (pregastrulation lethality) and humans (Seckel syndrome). Here we show that eliminating ATR in adult mice leads to defects in tissue homeostasis and the rapid appearance of age-related phenotypes, such as hair graying, alopecia, kyphosis, osteoporosis, thymic involution, fibrosis, and other abnormalities. Histological and genetic analyses indicate that ATR deletion causes acute cellular loss in tissues in which continuous cell proliferation is required for maintenance. Importantly, thymic involution, alopecia, and hair graying in ATR knockout mice were associated with dramatic reductions in tissue-specific stem and progenitor cells and exhaustion of tissue renewal and homeostatic capacity. In aggregate, these studies suggest that reduced regenerative capacity in adults via deletion of a developmentally essential DDR gene is sufficient to cause the premature appearance of age-related phenotypes.
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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
                21 July 2011
                : 6
                : 7
                Affiliations
                [1 ]Department of Immunology, Hospital of La Princesa, Sanitary Research Institute Princesa (IP), Autonomous University of Madrid, Madrid, Spain
                [2 ]Animal Facility, Autonomous University of Madrid, Madrid, Spain
                University of Pittsburgh, United States of America
                Author notes

                Conceived and designed the experiments: MM-M AE IS-A LA-A JA. Performed the experiments: MM-M AE IS-A LA-A AV-V SV. Analyzed the data: MM-M AE IS-A MOL JA. Contributed reagents/materials/analysis tools: AO EB AV-V SV EF CF-C. Wrote the paper: MM-M AE IS-A LA-A MOL JA.

                Article
                PONE-D-10-05971
                10.1371/journal.pone.0022589
                3141062
                21811636
                Miró-Murillo 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
                Biotechnology
                Genetic Engineering
                Genetically Modified Organisms
                Model Organisms
                Animal Models
                Molecular Cell Biology
                Cellular Types
                Muscle Cells
                Cellular Stress Responses

                Uncategorized

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