Crosstalk among Bcl-2 family members in B-CLL: seliciclib acts via the Mcl-1/Noxa axis and gradual exhaustion of Bcl-2 protection.
Cell Death Differ
; 14(11): 1958-67, 2007 Nov.
Article
en En
| MEDLINE
| ID: mdl-17703234
ABSTRACT
Seliciclib (R-roscovitine) is a cyclin-dependent kinase inhibitor in clinical development. It triggers apoptosis by inhibiting de novo transcription of the short-lived Mcl-1 protein, but it is unknown how this leads to Bax/Bak activation that is required for most forms of cell death. Here, we studied the effects of seliciclib in B-cell chronic lymphocytic leukemia (B-CLL), a malignancy with aberrant expression of apoptosis regulators. Although seliciclib-induced Mcl-1 degradation within 4 h, Bax/Bak activation occurred between 16 and 20 h. During this period, no transcriptional changes in apoptosis-related genes occurred. In untreated cells, prosurvival Mcl-1 was engaged by the proapoptotic proteins Noxa and Bim. Upon drug treatment, Bim was quickly released. The contribution of Noxa and Bim as a specific mediator of seliciclib-induced apoptosis was demonstrated via RNAi. Significantly, 16 h after seliciclib treatment, there was accumulation of Bcl-2, Bim and Bax in the 'mitochondria-rich' insoluble fraction of the cell. This suggests that after Mcl-1 degradation, the remaining apoptosis neutralizing capacity of Bcl-2 is gradually overwhelmed, until Bax forms large multimeric pores in the mitochondria. These data demonstrate in primary leukemic cells hierarchical binding and crosstalk among Bcl-2 members, and suggest that their functional interdependence can be exploited therapeutically.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Purinas
/
Leucemia Linfocítica Crónica de Células B
/
Apoptosis
/
Proteínas Proto-Oncogénicas c-bcl-2
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Inhibidores de Proteínas Quinasas
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Proteínas de Neoplasias
Límite:
Aged
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Aged80
/
Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Cell Death Differ
Año:
2007
Tipo del documento:
Article
País de afiliación:
Países Bajos