tailieunhanh - Báo cáo khoa học: Cleavage of focal adhesion proteins and PKCd during lovastatin-induced apoptosis in spontaneously immortalized rat brain neuroblasts

We have previously shown that lovastatin induces apoptosis in spontane-ously immortalized rat brain neuroblasts. Focal adhesion proteins and pro-tein kinase Cd(PKCd) have been implicated in the regulation of apoptosis. We found that lovastatin exposure induced focal adhesion kinase, Crk-asso-ciated substrate (p130 Cas ), PKCdcleavage and caspase-3 activation in a con-centration-dependent manner. Lovastatin effects were fully prevented by mevalonate. | ềFEBS Journal Cleavage of focal adhesion proteins and PKCÔ during lovastatin-induced apoptosis in spontaneously immortalized rat brain neuroblasts Lauro González-Fernández1 Maria Isabel Cerezo-Guisado2 Sonja Langmesser1 Maria Julia Bragado2 Maria Jesus Lorenzo2 and Luis Jesus Garcia-Marin1 1 Departamento de Fisiologia and 2 Departamento de Bioquimica y Biologia Molecular y Genetica Facultad de Veterinaria Universidad de Extremadura Caceres Spain Keywords apoptosis caspases lovastatin neuroblasts proteolysis Correspondence L. J. Garcia-Marin Departamento de Fisiologia Facultad de Veterinaria Avda. Universidad s n E-10071 Caceres Spain Fax 34 927 257110 Tel 34 927 257000 Ext. 1327 E-mail lgarcia@ Note These authors contributed equally to this work Received 13 July 2005 revised 27 September 2005 accepted 18 October 2005 doi We have previously shown that lovastatin induces apoptosis in spontaneously immortalized rat brain neuroblasts. Focal adhesion proteins and protein kinase CS PKCỖ have been implicated in the regulation of apoptosis. We found that lovastatin exposure induced focal adhesion kinase Crk-asso-ciated substrate p130Cas PKCS cleavage and caspase-3 activation in a concentration-dependent manner. Lovastatin effects were fully prevented by mevalonate. The cleavage of p130Cas was almost completely inhibited by z-DEVD-fmk a specific caspase-3 inhibitor and z-VAD-fmk a broad spectrum caspase inhibitor indicating that cleavage is mediated by caspase-3. In contrast the lovastatin-induced cleavage of PKCS was only blocked by z-VAD-fmk suggesting that PKCS cleavage is caspase-dependent but caspase-3-independent. Additionally z-VAD-fmk partially prevented lovastatin-induced neuroblast apoptosis. The present data show that lovastatin may induce neuroblast apoptosis by both caspase-dependent and independent pathways. These findings may suggest that the caspase-dependent component leading to the neuroblast cell death is likely to