| Autor: |
Frank Brand, Alisa Förster, Marc S. Raab, Michael Weller, Peter Claus, Carina M. Thome, Ruthild G. Weber, Andreas von Deimling, Martin Bucher, Manfred Westphal, Bettina Hentschel, Torsten Pietsch, Anne Kosfeld, Guido Reifenberger |
| Jazyk: |
angličtina |
| Rok vydání: |
2019 |
| Předmět: |
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| Zdroj: |
Neuro Oncol |
| Popis: |
In search of novel genes associated with glioma pathogenesis, we have previously shown that KIAA1797/FOCAD is frequently deleted in malignant gliomas and that the encoded focadhesin functions as a tumor suppressor impacting proliferation and migration of glioma cells in vitro and in vivo. Here, we examine an association of FOCAD copy number loss with overall survival of patients with astrocytic gliomas, and address the molecular mechanisms that govern the suppressive effect of focadhesin on glioma growth. FOCAD loss was associated with inferior outcome in patients with isocitrate dehydrogenase 1 or 2 (IDH)-mutant astrocytic gliomas of WHO grades II-IV. Multivariate analysis considering age at diagnosis, IDH mutation and MGMT promoter methylation status confirmed FOCAD loss as a prognostic factor for overall survival. Using a yeast two-hybrid screen and pull-down assays, we identified tubulin beta-6 and other tubulin family members as novel focadhesin-interacting partners. We demonstrate that tubulins and focadhesin co-localize at the centrosome and that focadhesin is enriched in proximity to centrioles. Focadhesin is recruited to microtubules via its interaction partner SLAIN motif family member 2 and reduces microtubule assembly rates, possibly explaining why focadhesin decreases cell migration. During the cell cycle, focadhesin levels peak in G2/M phase and influence time-dependent G2/M progression possibly via polo like kinase 1 phosphorylation, providing an explanation for focadhesin-dependent cell growth reduction. We conclude that FOCAD loss may promote biological aggressiveness and worsen clinical outcome of diffuse astrocytic gliomas by enhancing microtubule assembly and accelerating G2/M phase progression. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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