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  • 1
    Online Resource
    Online Resource
    Activation of Reg gene, a gene for insulin-producing β-cell regeneration: Poly(ADP-ribose) polymerase binds Reg promoter and regulates the transcription by autopoly(ADP-ribosyl)ation
    Proceedings of the National Academy of Sciences ; 2001
    In:  Proceedings of the National Academy of Sciences Vol. 98, No. 1 ( 2001-01-02), p. 48-53
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 98, No. 1 ( 2001-01-02), p. 48-53
    Abstract: The regeneration of pancreatic islet β cells is important for the prevention and cure of diabetes mellitus . We have demonstrated that the administration of poly(ADP-ribose) synthetase/polymerase (PARP) inhibitors such as nicotinamide to 90% depancreatized rats induces islet regeneration. From the regenerating islet-derived cDNA library, we have isolated Reg (regenerating gene) and demonstrated that Reg protein induces β-cell replication via the Reg receptor and ameliorates experimental diabetes. However, the mechanism by which Reg gene is activated in β cells has been elusive. In this study, we found that the combined addition of IL-6 and dexamethasone induced the expression of Reg gene in β cells and that PARP inhibitors enhanced the expression. Reporter gene assays revealed that the −81 ≈ −70 region (TGCCCCTCCCAT) of the Reg gene promoter is a cis -element for the expression of Reg gene. Gel mobility shift assays showed that the active transcriptional DNA/protein complex was formed by the stimulation with IL-6 and dexamethasone. Surprisingly, PARP bound to the cis -element and was involved in the active transcriptional DNA/protein complex. The DNA/protein complex formation was inhibited depending on the autopoly(ADP-ribosyl)ation of PARP in the complex. Thus, PARP inhibitors enhance the DNA/protein complex formation for Reg gene transcription and stabilize the complex by inhibiting the autopoly(ADP-ribosyl)ation of PARP.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.98.1.48
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2001
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
    Location Call Number Limitation Availability
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  • 2
    Online Resource
    Online Resource
    Isolation and characterization of a digoxin transporter and its rat homologue expressed in the kidney
    Proceedings of the National Academy of Sciences ; 2004
    In:  Proceedings of the National Academy of Sciences Vol. 101, No. 10 ( 2004-03-09), p. 3569-3574
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 101, No. 10 ( 2004-03-09), p. 3569-3574
    Abstract: Digoxin, which is one of the most commonly prescribed drugs for the treatment of heart failure, is mainly eliminated from the circulation by the kidney. P-glycoprotein is well characterized as a digoxin pump at the apical membrane of the nephron. However, little is known about the transport mechanism at the basolateral membrane. We have isolated an organic anion transporter (OATP4C1) from human kidney. Human OATP4C1 is the first member of the organic anion transporting polypeptide (OATP) family expressed in human kidney. The isolated cDNA encodes a polypeptide of 724 aa with 12 transmembrane domains. The genomic organization consists of 13 exons located on chromosome 5q21. Its rat counterpart, Oatp4c1, is also isolated from rat kidney. Human OATP4C1 transports cardiac glycosides (digoxin, K m = 7.8 μM and ouabain, K m = 0.38 μM), thyroid hormone (triiodothyronine, K m = 5.9 μM and thyroxine), cAMP, and methotrexate in a sodium-independent manner. Rat Oatp4c1 also transports digoxin ( K m = 8.0 μM) and triiodothyronine ( K m = 1.9 μM). Immunohistochemical analysis reveals that rat Oatp4c1 protein is localized at the basolateral membrane of the proximal tubule cell in the kidney. These data suggest that human OATP4C1/rat Oatp4c1 might be a first step of the transport pathway of digoxin and various compounds into urine in the kidney.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0304987101
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2004
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
    Location Call Number Limitation Availability
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    Online Resource
  • 3
    Online Resource
    Online Resource
    Keap1 degradation by autophagy for the maintenance of redox homeostasis
    Proceedings of the National Academy of Sciences ; 2012
    In:  Proceedings of the National Academy of Sciences Vol. 109, No. 34 ( 2012-08-21), p. 13561-13566
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 109, No. 34 ( 2012-08-21), p. 13561-13566
    Abstract: The Kelch-like ECH-associated protein 1 (Keap1)-NF-E2-related factor 2 (Nrf2) system is essential for cytoprotection against oxidative and electrophilic insults. Under unstressed conditions, Keap1 serves as an adaptor for ubiquitin E3 ligase and promotes proteasomal degradation of Nrf2, but Nrf2 is stabilized when Keap1 is inactivated under oxidative/electrophilic stress conditions. Autophagy-deficient mice show aberrant accumulation of p62, a multifunctional scaffold protein, and develop severe liver damage. The p62 accumulation disrupts the Keap1-Nrf2 association and provokes Nrf2 stabilization and accumulation. However, individual contributions of p62 and Nrf2 to the autophagy-deficiency–driven liver pathogenesis have not been clarified. To examine whether Nrf2 caused the liver injury independent of p62, we crossed liver-specific Atg7 :: Keap1-Alb double-mutant mice into p62 - and Nrf2 -null backgrounds. Although Atg7 :: Keap1-Alb :: p62 −/− triple-mutant mice displayed defective autophagy accompanied by the robust accumulation of Nrf2 and severe liver injury, Atg7 :: Keap1-Alb :: Nrf2 −/− triple-mutant mice did not show any signs of such hepatocellular damage. Importantly, in this study we noticed that Keap1 accumulated in the Atg7 - or p62 -deficient mouse livers and the Keap1 level did not change by a proteasome inhibitor, indicating that the Keap1 protein is constitutively degraded through the autophagy pathway. This finding is in clear contrast to the Nrf2 degradation through the proteasome pathway. We also found that treatment of cells with tert -butylhydroquinone accelerated the Keap1 degradation. These results thus indicate that Nrf2 accumulation is the dominant cause to provoke the liver damage in the autophagy-deficient mice. The autophagy pathway maintains the integrity of the Keap1-Nrf2 system for the normal liver function by governing the Keap1 turnover.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1121572109
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2012
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
    Location Call Number Limitation Availability
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    Online Resource
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