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| Author(s): |
Carolina Louzão Bigarella
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | Campinas, SP. |
| Institution: | Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Médicas |
| Defense date: | 2009-02-19 |
| Examining board members: |
Sara Teresinha Olalla Saad;
Mari Cleide Sogayar;
Roger Chammas;
José Barreto Campello Carvalheira;
Hernandes Faustino de Carvalho
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| Advisor: | Sara Teresinha Olalla Saad |
| Abstract | |
ARHGAP21 is a RhoGAP protein with GAP activity over Cdc42 and RhoA, it also interacts with ARF-GTPases and with a-catenin, controlling actin dynamics on Golgi membranes and the integrity of adherens junctions, respectively. Due to ARHGAP21 high expression levels in nervous tissues has emerged the objective of the present thesis that was evaluate the expression levels and the function of ARHGAP21 in the normal and neoplasic nervous system. Our results evidenced that ARHGAP21 localizes to the nucleus and perinuclear region of several cell types, and on cell protrusions in primary mouse neurons, and interacts with FAK in the perinuclear region. Results of ARHGAP21 depletion by shRNAi molecules evidenced that ARHGAP21 inhibits glioblastoma cell migration through the negative control of Cdc42, the inhibition of FAK?p130CAS signaling, and through the control of metaloprotease 2 secretion. Besides that, ARHGAP21 expression correlates to tumor grade on astrocytomas samples, indicating the existence of a negative control of ARHGAP21 on astrocytoma cellular transformation, since its depletion in vitro resulted in higher malignity of T98G glioblastoma cell line. In normal cerebral tissue, ARHGAP21 murine gene is highly expressed on E17 animals, day in which neuronal precursor's migration finishes and when there is a reduction in mmp-2 expression. Therefore, ARHGAP21 showed in normal nervous system, similar control of mmp-2 gene expression as observed in glioblastoma cell lines. Our results suggest that ARHGAP21 might be a master regulator of cellular migration in different tissues and, like this, it may has a crucial role in the control of tumor progression. (AU) | |