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Induction of apoptosis in cancer cells by tumor necrosis factor and butyrolactone, an inhibitor of cyclin-dependent kinases
Belizário, J. E; Sherwood, S; Beçak, W.
Afiliação
  • Belizário, J. E; Instituto Butantan. Laboratório de Genética.
  • Sherwood, S; Genentech, Inc.
  • Beçak, W; Instituto Butantan. Laboratório de Genética.
Braz. j. med. biol. res ; 32(4): 473-82, Apr. 1999. tab, ilus
Artigo em Inglês | LILACS, Sec. Est. Saúde SP | ID: lil-231741
Biblioteca responsável: BR1.1
RESUMO
Induction of apoptosis by tumor necrosis factor (TNF) is modulated by changes in the expression and activity of several cell cycle regulatory proteins. We examined the effects of TNF (1-100 ng/ml) and butyrolactone I (100 µM), a specific inhibitor of cyclin-dependent kinases (CDK) with high selectivity for CDK-1 and CDK-2, on three different cancer cell lines WEHI, L929 and HeLa S3. Both compounds blocked cell growth, but only TNF induced the common events of apoptosis, i.e., chromatin condensation and ladder pattern of DNA fragmentation in these cell lines. The TNF-induced apoptosis events were increased in the presence of butyrolactone. In vitro phosphorylation assays for exogenous histone H1 and endogenous retinoblastoma protein (pRb) in the total cell lysates showed that treatment with both TNF and butyrolactone inhibited the histone H1 kinase (WEHI, L929 and HeLa) and pRb kinase (WEHI) activities of CDKs, as compared with the controls. The role of proteases in the TNF and butyrolactone-induced apoptosis was evaluated by comparing the number and expression of polypeptides in the cell lysates by gel electrophoresis. TNF and butyrolactone treatment caused the disappearance of several cellular protein bands in the region between 40-200 kDa, and the 110- 90- and 50-kDa proteins were identified as the major substrates, whose degradation was remarkably increased by the treatments. Interestingly, the loss of several cellular protein bands was associated with the marked accumulation of two proteins apparently of 60 and 70 kDa, which may be cleavage products of one or more proteins. These findings link the decrease of cyclin-dependent kinase activities to the increase of protease activities within the growth arrest and apoptosis pathways induced by TNF.
Assuntos
Texto completo: Disponível Coleções: Bases de dados nacionais / Brasil Base de dados: LILACS / Sec. Est. Saúde SP Assunto principal: 4-Butirolactona / Fator de Necrose Tumoral alfa / Apoptose / Quinases Ciclina-Dependentes Tipo de estudo: Estudo prognóstico Limite: Animais / Humanos Idioma: Inglês Revista: Braz. j. med. biol. res Ano de publicação: 1999 Tipo de documento: Artigo / Documento de projeto
Texto completo: Disponível Coleções: Bases de dados nacionais / Brasil Base de dados: LILACS / Sec. Est. Saúde SP Assunto principal: 4-Butirolactona / Fator de Necrose Tumoral alfa / Apoptose / Quinases Ciclina-Dependentes Tipo de estudo: Estudo prognóstico Limite: Animais / Humanos Idioma: Inglês Revista: Braz. j. med. biol. res Ano de publicação: 1999 Tipo de documento: Artigo / Documento de projeto
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