Dokument: Rolle von Chronophin für die Cofilin-vermittelte Aktin-Dynamik in astrozytären Tumorzellen
| Titel: | Rolle von Chronophin für die Cofilin-vermittelte Aktin-Dynamik in astrozytären Tumorzellen | |||||||
| Weiterer Titel: | Role of Chronophin for cofilin-mediated actin dynamics in astrocytic tumour cells | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=12119 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20090721-092755-5 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Englisch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Fedorchenko, Oleg [Autor] | |||||||
| Dateien: |
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| Beitragende: | Prof. Dr. Gohla, Antje [Gutachter] Prof. Dr. Schmitt, Lutz [Gutachter] | |||||||
| Stichwörter: | Chronophin, CIN, Cofilin, Actin, Glioblastoma | |||||||
| Dewey Dezimal-Klassifikation: | 500 Naturwissenschaften und Mathematik » 570 Biowissenschaften; Biologie | |||||||
| Beschreibung: | Actin cytoskeletal dynamics are orchestrated by a large number of actin binding proteins. Among these, the actin depolymerizing factor cofilin is particularly important for stimulus-dependent actin remodelling. Chronophin (CIN) is a recently identified cofilin phosphatase of the haloacid dehalogenase (HAD) family of hydrolases that is highly expressed in brain. The CIN gene maps to human chromosome 22q13.1 in a region that is frequently deleted in astrocytic gliomas. Interestingly, the frequency of loss of heterozygosity (LOH) on chromosome 22q12.3 strongly increases with the tumor malignancy grade, suggesting the presence of a hitherto unidentified astrocytoma tumor suppressor gene. We have analyzed the expression of cofilin regulatory proteins in tumor samples from patients with astrocytic gliomas of different malignancy grades. Using a newly developed CIN rabbit monoclonal antibody, we were able to show that CIN expression was strongly reduced in the majority of grade III and grade IV astrocytomas. In contrast, the expression of the functional CIN antagonist LIMK and its upstream regulator Pak4 was increased in ~50% of the investigated samples. These results suggest a dysregulation of cofilin-dependent actin dynamics in astrocytic gliomas. To investigate the role of CIN in astrocytic tumors on a cellular level, we have depleted CIN by RNA interference in the astrocytoma cell line GBM 6840. Interestingly, the reduction of CIN levels increased colony formation of these cells in soft agar, suggesting a role for CIN in tumor initiation. Furthermore, the depletion of CIN increased tumor cell invasion through matrigel and elevated the percentage of aneuploid cells with nuclear deformities, which are clinically relevant markers of glioblastomas. Together, our results show for the first time a dysregulation of cofilin-dependent actin dynamics in astrocytic gliomas and suggest a function for CIN as an astrocytoma tumor suppressor gene. | |||||||
| Rechtliche Vermerke: | Aus patentrechtl. Gründen bis 31.12.2009 gesperrt | |||||||
| Lizenz: |  Urheberrechtsschutz | |||||||
| Fachbereich / Einrichtung: | Medizinische Fakultät » Institute » Institut für Biochemie und Molekularbiologie II | |||||||
| Dokument erstellt am: | 02.07.2010 | |||||||
| Dateien geändert am: | 14.07.2009 | |||||||
| Promotionsantrag am: | 15.05.2009 | |||||||
| Datum der Promotion: | 22.06.2009 |
