Publications (17) View all
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Article: Novel Higher-Order Epigenetic Regulation of the Bdnf Gene upon Seizures.
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ABSTRACT: Studies in cultured cells have demonstrated the existence of higher-order epigenetic mechanisms, determining the relationship between expression of the gene and its position within the cell nucleus. It is unknown, whether such mechanisms operate in postmitotic, highly differentiated cell types, such as neurons in vivo. Accordingly, we examined whether the intranuclear positions of Bdnf and Trkb genes, encoding the major neurotrophin and its receptor respectively, change as a result of neuronal activity, and what functional consequences such movements may have. In a rat model of massive neuronal activation upon kainate-induced seizures we found that elevated neuronal expression of Bdnf is associated with its detachment from the nuclear lamina, and translocation toward the nucleus center. In contrast, the position of stably expressed Trkb remains unchanged after seizures. Our study demonstrates that activation-dependent architectural remodeling of the neuronal cell nucleus in vivo contributes to activity-dependent changes in gene expression in the brain.Journal of Neuroscience 02/2013; 33(6):2507-11. · 7.11 Impact Factor -
Article: Influence of matrix metalloproteinase MMP-9 on dendritic spine morphology.
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ABSTRACT: An increasing body of data has shown that matrix metalloproteinase-9 (MMP-9), an extracellularly acting, Zn(2+)-dependent endopeptidase, is important not only for pathologies of the central nervous system but also for neuronal plasticity. Here, we use three independent experimental models to show that enzymatic activity of MMP-9 causes elongation and thinning of dendritic spines in the hippocampal neurons. These models are: a recently developed transgenic rat overexpressing autoactivating MMP-9, dissociated neuronal cultures, and organotypic neuronal cultures treated with recombinant autoactivating MMP-9. This dendritic effect is mediated by integrin β1 signalling. MMP-9 treatment also produces a change in the decay time of miniature synaptic currents; however, it does not change the abundance and localization of synaptic markers in dendritic protrusions. Our results, considered together with several recent studies, strongly imply that MMP-9 is functionally involved in synaptic remodelling.Journal of Cell Science 09/2011; 124(Pt 19):3369-80. · 6.11 Impact Factor -
Article: Deleted in liver cancer protein family in human malignancies (Review).
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ABSTRACT: The Deleted in Liver Cancer (DLC) protein family comprises proteins that exert their function mainly by the Rho GTPase-activating protein (GAP) domain and by regulation of the small GTPases. Since Rho GTPases are key factors in cell proliferation, polarity, cytoskeletal remodeling and migration, the aberrant function of their regulators may lead to cell transformation. One subgroup of these proteins is the DLC family. It was found that the first identified gene from this family, DLC1, is often lost in hepatocellular carcinoma and may be involved as a tumor suppressor in the liver. Subsequent studies evaluated the hypothesis that the DLC1 gene acts as a tumor suppressor, not only in liver cancer, but also in other types of cancer. Following DLC1, two other members of the DLC protein family, DLC2 and DLC3, were identified. However, limited published data are available concerning the role of these proteins in malignant transformation. This review focuses on the structure and the role of DLC1 and its relatives in physiological conditions and summarizes data published thus far regarding DLC function in the neoplastic process.Oncology letters 09/2011; 2(5):763-768. · 0.11 Impact Factor -
Article: Up-regulation of CacyBP/SIP during rat breast cancer development.
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ABSTRACT: BACKGROUND: CacyBP/SIP (calcyclin binding protein/Siah-1 interacting protein) was originally discovered in Ehrlich ascities tumor cells but was later found also in many different tumors. METHODS: To better understand the function of CacyBP/SIP in carcinogenesis, we used immunohistochemistry, Western blotting, and RT-PCR assays to study the distribution and level of CacyBP/SIP in mammary tissues after tumor induction in rat with DMBA [(dimethylbenz[a]anthracene)]. Application of such a model allowed us to monitor changes in CacyBP/SIP level during development of breast cancer. RESULTS: We found that both the protein and mRNA levels of CacyBP/SIP gradually increased in pathologically changed tissues and were highest in tumors taken 8 weeks after DMBA treatment. Similar changes as for CacyBP/SIP were detected in the level of β-catenin. CONCLUSION: Increase in CacyBP/SIP expression during development of breast cancer, observed early in the mammary tissues with only minimal pathological changes, might suggest an important role of this protein in the process of carcinogenesis.Breast Cancer 08/2012; · 1.36 Impact Factor -
Article: Prenyltransferases Regulate CD20 Protein Levels and Influence Anti-CD20 Monoclonal Antibody-mediated Activation of Complement-dependent Cytotoxicity.
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ABSTRACT: Anti-CD20 monoclonal antibodies (mAbs) are successfully used in the management of non-Hodgkin lymphomas and chronic lymphocytic leukemia. We have reported previously that statins induce conformational changes in CD20 molecules and impair rituximab-mediated complement-dependent cytotoxicity. Here we investigated in more detail the influence of farnesyltransferase inhibitors (FTIs) on CD20 expression and antitumor activity of anti-CD20 mAbs. Among all FTIs studied, L-744,832 had the most significant influence on CD20 levels. It significantly increased rituximab-mediated complement-dependent cytotoxicity against primary tumor cells isolated from patients with non-Hodgkin lymphomas or chronic lymphocytic leukemia and increased CD20 expression in the majority of primary lymphoma/leukemia cells. Incubation of Raji cells with L-744,832 led to up-regulation of CD20 at mRNA and protein levels. Chromatin immunoprecipitation assay revealed that inhibition of farnesyltransferase activity was associated with increased binding of PU.1 and Oct-2 to the CD20 promoter sequences. These studies indicate that CD20 expression can be modulated by FTIs. The combination of FTIs with anti-CD20 mAbs is a promising therapeutic approach, and its efficacy should be examined in patients with B-cell tumors.Journal of Biological Chemistry 07/2012; 287(38):31983-93. · 4.77 Impact Factor
