LSD1 controls metastasis of androgen-independent prostate cancer cells through PXN and LPAR6

Lysine-specific demethylase 1 (LSD1) was shown to control gene expression and cell proliferation of androgen-dependent prostate cancer (PCa) cells, whereas the role of LSD1 in androgen-independent metastatic prostate cancer remains elusive. Here, we show that depletion of LSD1 leads to increased migration and invasion of androgen-independent PCa cells. Transcriptome and cistrome analyses reveal that LSD1 regulates expression of lysophosphatidic acid receptor 6 (LPAR6) and cytoskeletal genes including the focal adhesion adaptor protein paxillin (PXN). Enhanced LPAR6 signalling upon LSD1 depletion promotes migration with concomitant phosphorylation of PXN. In mice LPAR6 overexpression enhances, whereas knockdown of LPAR6 abolishes metastasis of androgen-independent PCa cells. Taken together, we uncover a novel mechanism of how LSD1 controls metastasis and identify LPAR6 as a promising therapeutic target to treat metastatic prostate cancer

Kumulierter Energieaufwand - Gussteilfertigung. Bd. 1. Teilthema: Methodik der Auswertung und Analyse von Giessereien. Bd. 2. Teilthema: Energieaufwand in der spanabhebenden Teilefertigung. Bd. 3. Teilthema: Entwicklung eines Modells zur Stoff- und Energiemengenanalyse fuer die Herstellung von Gussteilen Abschlussbericht

Development of materials, energy and carbon dioxide balances, acquisition and recording of data on casting and metal cutting processes, with selected examples of the 9 participating partners of the casting industry.Erarbeitung von Stoff-, Energie- und CO_2-Bilanzen, Erfassung und Ermittlung von Daten fuer die Formgebung durch Giessen und die spangebende Bearbeitung an ausgewaehlten Beispielen der 9 beteiligten Firmen der Giessereiindustrie. (orig.)Published in three separate volumesSIGLEAvailable from TIB Hannover: F01B720: F01B721: F01B722 / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekDeutsche Bundesstiftung Umwelt, Osnabrueck (Germany)DEGerman

Selective inactivation of USP18 isopeptidase activity in vivo enhances ISG15 conjugation and viral resistance.

Protein modification by the ubiquitin-like protein ISG15 is an interferon (IFN) effector system, which plays a major role in antiviral defense. ISG15 modification is counteracted by the isopeptidase USP18, a major negative regulator of IFN signaling, which was also shown to exert its regulatory function in an isopeptidase-independent manner. To dissect enzymatic and nonenzymatic functions of USP18 in vivo, we generated knock-in mice (USP18(C61A/C61A)) expressing enzymatically inactive USP18. USP18(C61A/C61A) mice displayed increased levels of ISG15 conjugates, validating that USP18 is a major ISG15 isopeptidase in vivo. Unlike USP18(-/-) mice, USP18(C61A/C61A) animals did not exhibit morphological abnormalities, fatal IFN hypersensitivity, or increased lethality, clearly showing that major USP18 functions are unrelated to its protease activity. Strikingly, elevated ISGylation in USP18(C61A/C61A) mice was accompanied by increased viral resistance against vaccinia virus and influenza B virus infections. Enhanced resistance upon influenza B infection in USP18(C61A/C61A) mice was completely reversed in USP18(C61A/C61A) mice, which additionally lack ISG15, providing evidence that the observed reduction in viral titers is ISG15 dependent. These results suggest that increasing ISGylation by specific inhibition of USP18 protease activity could constitute a promising antiviral strategy with only a minimal risk of severe adverse effects

PRK1/PKN1 controls migration and metastasis of androgen-independent prostate cancer cells

The major threat in prostate cancer is the occurrence of metastases in androgen-independent tumor stage, for which no causative cure is available. Here we show that metastatic behavior of androgen-independent prostate tumor cells requires the protein-kinase-C-related kinase (PRK1/PKN1) in vitro and in vivo. PRK1 regulates cell migration and gene expression through its kinase activity, but does not affect cell proliferation. Transcriptome and interactome analyses uncover that PRK1 regulates expression of migration-relevant genes by interacting with the scaffold protein sperm-associated antigen 9 (SPAG9/JIP4). SPAG9 and PRK1 colocalize in human cancer tissue and are required for p38-phosphorylation and cell migration. Accordingly, depletion of either ETS domain-containing protein Elk-1 (ELK1), an effector of p38-signalling or p38 depletion hinders cell migration and changes expression of migration-relevant genes as observed upon PRK1-depletion. Importantly, a PRK1 inhibitor prevents metastases in mice, showing that the PRK1-pathway is a promising target to hamper prostate cancer metastases in vivo

The Europeanization of Welfare - The Domestic Impact of Intra-European Social Security

Studies of Europeanization have demonstrated that the impact of European integration differs between Member States and across policies. Although Europeanization research has been expanded and clarified in recent years, we still know relatively little about the factors mediating the national processes of change that thus condition impact. This article examines the impact of European social security integration on national welfare institutions in Denmark and Germany, and it traces the Europeanization process, which may explain the diverging impact of a common input in these two Member States. In order to understand how the same process of integration may cause a diverging impact on national institutions, two sets of mediating factors are examined: firstly, the institutional and "de facto" exposedness to European integration; and, secondly, the national political, administrative and legal responses to integration. It is argued that these intervening variables are decisive for how common European demands are mediated nationally and are likely to explain impact variations referring to the same cause. Copyright 2005 Blackwell Publishing Ltd.