Geldanamycin, a heat-shock protein 90-binding agent, induces thymocyte apoptosis through destabilization of Lck in presence of 12-O-tetradecanoylphorbol 13-acetate.
Biomed Res
; 28(1): 33-42, 2007 Feb.
Article
em En
| MEDLINE
| ID: mdl-17379955
ABSTRACT
Geldanamycin, a heat-shock protein 90 (Hsp90)-binding agent, modulates various cellular activities. The present study found that, although geldanamycin by itself had no effect on thymocyte viability, it induced apoptosis in thymocytes with a reduction of the mitochondrial transmembrane potential (DeltaPsim) in the presence of 12-O-tetradecanoylphorbol 13-acetate (TPA), an activator of protein kinase C (PKC). This apoptosis depended on transcription and translation, and on activation of caspase-8 and -3. Geldanamycin treatment in the presence of TPA also enhanced destabilization of Lck. This destabilization was independent of transcription and translation. It was inhibited, however, by conventional PKC inhibitors, preventing apoptosis. Proteasome inhibitor affected neither the degradation of Lck nor DNA fragmentation, although they inhibited reduction of DeltaPsim. These results suggest that the ubiquitin-proteasome system is not involved in Lck destabilization, and that DeltaPsim reduction is not directly related to the progression of apoptosis. Furthermore, inhibition of Lck in the presence of TPA induced apoptosis in thymocytes. Our findings suggest that Hsp90 modulates thymocyte apoptosis in concert with PKC through the destabilization of Lck and in a caspase-8- and -3-dependent manner.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Timo
/
Acetato de Tetradecanoilforbol
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Benzoquinonas
/
Apoptose
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Proteínas de Choque Térmico HSP90
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Proteína Tirosina Quinase p56(lck) Linfócito-Específica
/
Lactamas Macrocíclicas
Limite:
Animals
Idioma:
En
Ano de publicação:
2007
Tipo de documento:
Article