Caspase-3 activation is an early event and initiates apoptotic damage in a human leukemia cell line

Varghese, J. ; Khandre, N. S. ; Sarin, A. (2003) Caspase-3 activation is an early event and initiates apoptotic damage in a human leukemia cell line Apoptosis, 8 (4). pp. 363-370. ISSN 1360-8185

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Many apoptotic pathways culminate in the activation of caspase cascades usually triggered by the apical caspases-8 or -9. We describe a paradigm where apoptosis is initiated by the effector caspase-3. Diethylmaleate (DEM)-induced apoptotic damage in Jurkat cells was blocked by the anti-apoptotic protein Bcl-2, whereas, a peptide inhibitor of caspase-3 but not caspase-9 blocked DEM-induced mitochondrial damage. Isogenic Jurkat cell lines deficient for caspase-8 or the adaptor FADD (Fas associated death domain) were not protected from DEM-induced apoptosis. Caspase-3 activation preceded that of caspase-9 and initial processing of caspase-3 was regulated independent of caspase-9 and Bcl-2. However, inhibitors of caspase-9 or caspase-6 regulated caspase-3 later in the pathway. We explored the mechanism by which caspase-3 processing is regulated in this system. DEM triggered a loss of Erk−½ phosphorylation and XIAP (X-linked inhibitor of apoptosis protein) expression. The phorbol ester PMA activated a MEK-dependent pathway to block caspase-3 processing and cell death. Constitutively active MEK-1 (CA-MEK) upregulated XIAP expression and exogenous XIAP inhibited DEM-induced apoptotic damage. Thus, we describe a pathway where caspase-3 functions to initiate apoptotic damage and caspase-9 and caspase-6 amplify the apoptotic cascade. Further, we show that MEK may regulate caspase-3 activation via the regulation of XIAP expression in these cells.

Item Type:Article
Source:Copyright of this article belongs to Springer.
Keywords:Apoptosis; Bcl-2; Caspase-3; Erk; Mitochondria; T Cells
ID Code:62144
Deposited On:19 Sep 2011 11:49
Last Modified:19 Sep 2011 11:49

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