Defects in regulation of apoptosis in caspase-2-deficient mice

Abstract

During embryonic development, a large number of cells die naturally to shape the new organism. Members of the caspase family of proteases are essential intracellular death effectors. Herein, we generated caspase-2-deficient mice to evaluate the requirement for this enzyme in various paradigms of apoptosis. Excess numbers of germ cells were endowed in ovaries of mutant mice and the oocytes were found to be resistant to cell death following exposure to chemotherapeutic drugs. Apoptosis mediated by granzyme B and perforin was defective in caspase-2-deficient B lymphoblasts. In contrast, cell death of motor neurons during development was accelerated in caspase-2-deficient mice. In addition, caspase-2-deficient sympathetic neurons underwent apoptosis more effectively than wild-type neurons when deprived of NGF. Thus, caspase-2 acts both as a positive and negative cell death effector, depending upon cell lineage and stage of development.

Caspase-2 as a tumour suppressor

“…9 However, as discussed below, deletion of caspase-2 in mice does not lead to a phenotype that would support a broad function for this caspase in apoptosis. 10 A potential function of caspase-2 in tumour suppression was first suggested in 1995, and a number of subsequent correlative studies with clinical samples have followed. [11][12][13][14] However, more definitive experimental studies were first published in 2009, in which we presented data for the first time to show a potential tumour suppressor function for caspase-2.…”

“…10,16 Casp2 À / À mice have excess numbers of germ cells in ovaries, and caspase-2-deficient oocytes have been reported to be somewhat resistant to apoptosis induced by chemotherapeutic drugs. 10 However, most cell types in wild-type and Casp2 À / À mice, including thymocytes and DRG neurons, show comparable levels of cell death in response to various cytotoxic stimuli. 16 Further, Casp2 À / À ; Casp9 À / À double knockout mice are indistinguishable from Casp9 À / À mice in terms of their development and show embryonic brain malformation and perinatal lethality.…”

Molecular requirements for doxorubicin-mediated death in murine oocytes

“…3,10,[20][21][22] We focused on describing characteristics of apoptosis: mainly morphological changes (e.g., condensation, budding and cellular fragmentation) and biochemical alterations (i.e., DNA cleavage using Comet Assay Kit, Trevigen, Gaithersburg, MD, USA). Analysis of the comets to generate quantitative data was performed using a computer-based program (Duty et al 36 VisComet; Impuls Computergestutzte Bildanalyse GmbH, Gilching, Germany).…”

“…Those experiments confirmed the importance of Bax, Caspase-2 and ceramide, but excluded p53 and Caspase-3 as important effectors in cytoplasmic fragmentation. 3,10,[20][21][22] In the current report, we attempted to further dissect some mechanistic aspects of the molecular pathways underlying cytoplasmic fragmentation of oocytes during the course of treatment with DXR, including: requirements of spindle checkpoints; exit from meiosis; analysis of gene expression; as well as the role of sphingolipids.…”

Caspases on the brain

“…The timing of death varies among regions of the brain, from the early embryonic to the early postnatal periods. Mice lacking many of the other caspases, such as caspase 1, 2, 6, 11, or 12, do not have an obvious neuronal phenotype (Kuida et al, 1995;Bergeron et al, 1998;Namura et al, 1998;Wang et al, 1998;Zheng et al, 2000), but these caspases may play a role in regional pruning of neurons or in the plasticity of the nervous system.…”