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1.
Biochim Biophys Acta ; 1359(1): 13-24, 1997 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-9398081

RESUMO

Lovastatin, an inhibitor of protein prenylation, was reported to inhibit DNA synthesis and induce apoptosis in cultured cells. This report describes the morphological consequences of lovastatin treatment. Lovastatin (50 microM) induced mesangial cell rounding and disassembly of actin stress fibers within 24 to 48 h. After 48 to 72 h of lovastatin treatment, the cells detached from the substratum and underwent apoptotic cell death as evidenced by condensed nuclear chromatin, nuclear fragmentation, cell blebbing and decrease in cell size. Time lapse cinematography revealed that lovastatin caused cell rounding by either inhibiting cytokinesis or cell spreading following cytokinesis. Lovastatin-induced cell rounding, detachment, and apoptosis were dependent upon cell proliferation. These effects were prevented by serum deprivation to inhibit cell proliferation or by plating cells at densities which resulted in contact inhibition of cell growth. Lovastatin-induced mesangial cell rounding and apoptosis were also prevented by the inclusion of the isoprenoids all-trans-farnesol or all-trans-geranylgeraniol in the incubation medium. These results indicate that the effects of lovastatin were mediated by inhibition of protein isoprenylation because exogenous all-trans-geranylgeraniol can be used only in protein prenylation. The small GTP-binding protein RhoA, which may be important for cell spreading and cytokinesis, accumulated in the cytosol following treatment with lovastatin, suggestive of its inactivation. This effect was also prevented by the inclusion of either farnesol or geranylgeraniol in the incubation medium. Thus, lovastatin-induced apoptosis in mesangial cells occurs by interfering with prenylation dependent mitotic and post-mitotic events.


Assuntos
Apoptose/efeitos dos fármacos , Mesângio Glomerular/efeitos dos fármacos , Lovastatina/farmacologia , Mitose/efeitos dos fármacos , Actinas/metabolismo , Actinas/ultraestrutura , Animais , Bromodesoxiuridina/farmacologia , Contagem de Células/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Tamanho Celular/efeitos dos fármacos , Células Cultivadas , Diterpenos/farmacologia , Farneseno Álcool/farmacologia , Proteínas de Ligação ao GTP/metabolismo , Mesângio Glomerular/citologia , Microscopia Eletrônica , Microscopia de Vídeo , Prenilação de Proteína/efeitos dos fármacos , Ratos , Proteína rhoA de Ligação ao GTP
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