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J Cell Sci ; 117(Pt 24): 5815-23, 2004 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-15507484

RESUMEN

Beta1-integrin protects keratinocyte stem cells (KSC) from cell-detachment apoptosis ('anoikis'). Here we show that caspase-8 active protein is detected in both young transit amplifying (TA) cells and TA cells, but not in KSC. On suspension, caspases are activated earlier in young TA than in KSC, whereas anti-beta1-integrin neutralizing antibody accelerates caspase activation in both KSC and young TA. Caspases 8 and 10 are the first caspases to be activated whereas caspase-8 inhibitor zIETD-fmk delays the activation of Bid, caspase-9 and caspase-3. However, the caspase-9 inhibitor zLEDH-fmk does not block the activation of caspase-8, Bid, caspase-10 and caspase-3. Moreover, caspase-8, but not caspase-9 inhibitor partially prevents keratinocyte anoikis. As FLIP inhibits caspase-8 processing, we retrovirally infected HaCaT keratinocytes with c-FLIP(L). Anti-beta1-integrin fails to activate caspase-8, Bid, caspase-9 and to induce the release of cytochrome c in c-FLIP(L) overexpressing keratinocytes. Finally, overexpression of c-FLIP(L) partially prevents anoikis in both suspended and anti-beta1 integrin-treated cells. Taken together, these results indicate that the extrinsic apoptotic pathway triggered by caspase-8 predominates in keratinocyte anoikis. However, the release of cytochrome c and the later activation of caspase-9 seem to suggest that the intrinsic mitochondrial pathway may intervene as a positive feedback loop of caspase activation.


Asunto(s)
Caspasas/metabolismo , Integrina beta1/metabolismo , Queratinocitos/citología , Anoicis , Proteínas Reguladoras de la Apoptosis , Proteína Proapoptótica que Interacciona Mediante Dominios BH3 , Western Blotting , Proteína Reguladora de Apoptosis Similar a CASP8 y FADD , Proteínas Portadoras/metabolismo , Caspasa 10 , Caspasa 3 , Caspasa 8 , Caspasa 9 , Muerte Celular , Línea Celular , Células Cultivadas , Citosol/metabolismo , Activación Enzimática , Inhibidores Enzimáticos/farmacología , Humanos , Inmunohistoquímica , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Queratinocitos/metabolismo , Glicoproteínas de Membrana/metabolismo , Mitocondrias/metabolismo , Retroviridae/metabolismo , Ligando Inductor de Apoptosis Relacionado con TNF , Factores de Tiempo , Factor de Necrosis Tumoral alfa/metabolismo
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