Role of ARHGAP21 and FMNL1 proteins in Rho GTPases signalling and cancer progression

• Grant number: 10/51472-1
• Support Opportunities: Regular Research Grants
• Start date: September 01, 2010
• End date: August 31, 2013
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Agreement: King's College London
• Principal Investigator: Sara Teresinha Olalla Saad
• Grantee: Sara Teresinha Olalla Saad
• Principal researcher abroad: Anne Ridley
• Institution abroad: King's College London, England
• Host Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 05/51681-1 - Functional investigation and characterization of the involvement of novel target genes and new therapeutics for myelodysplastic and leukemia lineages, AP.TEM

Abstract

Among the various Genome Projects developed in Brazil, the Human Cancer Genome Project stands out. This project is of great value, given that many new genes found altered in cancer were identified. Over the last few years our research group has been characterizing several novel genes, based on a search of the ORESTES database, generated from the Human Cancer Genome Project, for ESTs similar to known cytoskeletal proteins (or related proteins), expressed in bone marrow cancers. One of these genes encodes the Rho GTPase-Activating Protein 21 (ARHGAP21) that is a GTPase activating protein (GAP) for the Rho GTPases Cdc42 and RhoA. Rho GTPase proteins are key regulators of the cytoskeleton and known to contribute to of cancer progression, including the loss of growth control and acquisition of an invasive phenotype. For example, the increased activity of these proteins results in increased mobility in invasive tumors. We have shown that ARHGAP21 is highly expressed in brain and cardiac tissues in comparison with hematopoietic tissues, however there is an increase in its expression on IIL-60 cells submitted to differentiation with ATRA. In addition we have shown that ARHGAP21 protein interacts with focal adhesion kinase (FAK) and with the protein kinase C isotype zeta (PKC) and that knockdown of ARHGAP21 in glioblastoma cells increases FAK activity and migration of these cells. Other recent results display differential subcellular localization of ARHGAP21 in hematopoietic cells: although localized in the membrane and cytoplasm of peripheral blood mononuclear cells (PBMCs) from healthy donors, ARHGAP21 is also present in the nuclear compartment of CD34+ MDS cells (Barcellos et al., unpublished results)… (AU)