Caspase-2 is a member of the CED-3/caspase (cysteine aspartic acid specific protease) family of enzymes. Alternative splicing gives rise to a long (caspase-2L, pro-apoptotic) and short/truncated (caspase-2S, anti-apoptotic) form. Original cloning of the gene was reported in 1994 (Wang et al. 1994 ).
NCBI Summary:
This gene encodes a protein which is a member of the cysteine-aspartic acid protease (caspase) family. Sequential activation of caspases plays a central role in the execution-phase of cell apoptosis. Caspases exist as inactive proenzymes which undergo proteolytic processing at conserved aspartic residues to produce 2 subunits, large and small, that dimerize to form the active enzyme. The proteolytic cleavage of this protein is induced by a variety of apoptotic stimuli. Alternative splicing of this gene results in four transcript variants which encode different isoforms.
Caspase-2, expressed principally as the long or pro-apoptotic form in vertebrates (see above), is a component of the caspase cascade involved in the execution phase of apoptosis. The pro-form of the enzyme is activated during apoptosis by caspase-9 (Slee et al. 1999 ) or a caspase-3-like enzyme (Li et al. 1997 ).
Cellular localization
Cytoplasmic, Mitochondrial
Comment
Release of caspase-2 from mitochondria during the execution phase of apoptosis has been reported (Susin et al. 1999 ). This observation may be relevant to the findings that recruitment of the upstream adapter protein, Apaf-1, by mitochondrial cytochrome c release is required for efficient processing of caspase-2 and/or its activators (Yoshida et al. 1998 ).
Ovarian function
Follicle atresia, Luteolysis, Oocyte apoptosis
Comment
Several caspases, including caspase-2, have been implicated in granulosa cell death during atresia of maturing antral follicles in the rat (Flaws et al. 1995 ), and in oocyte apoptosis occurring developmentally (Bergeron et al. 1998 ) as well as in response to anticancer therapy (Perez et al. 1997 and Bergeron et al. 1998 ). Peptide inhibitors that inactivate caspase-2 and/or prevent its processing (Li et al. 1997 ) have also been reported to suppress granulosa cell during atresia of mouse antral follicles in vitro (Maravei DV, Trbovich AM, Perez GI, Tilly KI, Talanian RV, Banach D, Wong WW, Tilly JL. Cleavage of cytoskeletal proteins by caspases during ovarian cell death: evidence that cell-free systems do not always mimic apoptotic events in intact cells. Cell Death Differ 1997; 4: 707-712 - no Medline hyperlink available). For recent reviews on the role(s) of caspases in oocyte death see Morita and Tilly (1999 ), and on the role(s) of caspases in granulosa cell death see Tilly and Robles (Tilly JL, Robles R. Apoptosis and its impact in clinical reproductive medicine. In: Molecular Biology in Reproductive Medicine. BCJM Fauser, AJ Rutherford, JF Strauss III, A Van Steirteghem, (eds.), Parthenon Publishing: New York 1999; pp 79-101 - no Medline hyperlink available). Caspase-2 involvement during ionizing radiation-induced oocyte death in the mouse ovary. Hanoux V et al. In mammals, the pool of primordial follicles at birth is determinant for female fertility. Exposure to IR during oogonia proliferation and the diplotene stages of ovarian development induced the virtual disappearance of primordial follicles in the postnatal ovary, while half the follicular reserve remained present after irradiation during the zygotene/pachytene stages. This sensitivity difference was correlated with the level of caspase-2 expression evaluated by immunohistochemistry. At the diplotene stage, Western blot and caspase activity analysis revealed that caspase-2 was activated 2 h after irradiation and a significant increase in the number of oocytes expressing cleaved caspase-9 and -3 occurred 6 h after treatment. Inhibition of caspase-2 activity prevented the cleavage of caspase-9 and partially prevented the loss of oocytes in response to irradiation. Taken together, our results show that caspase-2-dependent activation of the mitochondrial apoptotic pathway is one of the mechanisms involved in the genotoxic stress-induced depletion of the primordial follicle pool.Cell Death and Differentiation advance online publication, 3 November 2006; doi:10.1038/sj.cdd.4402052.
Activity and expression of different members of the caspase family in the rat corpus luteum (CL) during pregnancy and postpartum. Peluffo MC et al. Studies were designed to examine the expression and activity of four caspases, which contribute to the initial (caspases-2, -8 and -9) and final (caspase-3) events in apoptosis, in the rat CL during pregnancy (days, 7, 17, 19 and 21 of gestation), postpartum (day 1 and 4) and after injection (0, 8, 16, 24 and 36 h) of the physiological luteolysin, PGF-2alpha. In addition, the temporal relationship of caspase expression/activity relative to steroid production and luteal regression was evaluated. During pregnancy, the activity of all four caspases was significantly greater on day 19, prior to a decline in CL progesterone (P) and CYP11A1 levels at day 21 of gestation. The levels of the caspase-3 active fragment (p17, measured by Western blot) also increased at day 19 and 21 of pregnancy. Immunohistochemical analyses detected specific staining for the caspases in luteal cells (large and small), as well as, in endothelial cells. However, the percentage of apoptotic cells did not increase in the CL until postpartum. Following PGF-2alpha injection, there was a significant decrease in CL P by 24 h, though the activity of all four caspases did not increase until 36 h post treatment. The active p17 fragment of caspase-3 also significantly increased at 36 h post- PGF-2alpha. These results suggest that an increase in the activity of caspase-2, -8, -9 and -3 is associated with the early events of natural luteolysis at the end of pregnancy. Also the exogenous administration of the luteolysin PGF-2alpha may regulate members of the caspase family. Key words: caspases, luteolysis, corpus luteum, pregnancy.
Expression regulated by
FSH, LH
Comment
Levels of caspase-2 (long isoform) have been reported to decrease in the prepubertal rat ovary following in vivo administration of equine chorionic gonadotropin, coincident with a suppression of apoptosis (Flaws et al. 1995 ).
Expression of caspase-2 mRNA (long and short isoforms) has been identified in whole ovarian homogenates prepared from prepubertal female rats (Flaws et al. 1995 ), avian granulosa and theca-interstitial cells (Johnson et al. 1997 ), adult human ovaries and granulosa-lutein cells (Kugu et al. 1998 ) and murine oocytes (Bergeron et al. 1998 ).
Follicle stages
Corpus luteum
Comment
Expression of caspase-2, -3, -8 and -9 proteins and enzyme activity in the corpus luteum of the rat at different stages during the natural estrous cycle. Peluffo MC et al. Apoptosis is associated with the regression of the corpus luteum (CL) in many species. Since caspases play a central role in apoptosis, we studied several initiators (-2, -8, and -9) and the main effector (-3) caspase in the CL during the estrous cycle of the rat. Two different populations of CL (old and new) were identified on ovaries at estrus and diestrus II (DII). Diminished (P < 0.05) luteal progesterone content and P450scc levels suggested that functional luteolysis occurred between the new CL at DII and old CL at estrus, whereas the decline (P < 0.05) in luteal weight indicated that structural regression was occurring between old CL at estrus to DII. Immunostaining for caspase-2 in luteal and endothelial cells appeared to increase as the luteal phase progressed, peaking at DII in the old CL. However, caspase-8 and -9 immunostaining showed little change with a slight increase at estrus in the old population. Notably, caspase-3 staining appeared to peak at DII in the new CL. Enzyme activity of caspase-9 increased (P < 0.05) in the new CL at DII, followed by that of caspase-2 and -3 in old CL at estrus. Caspase-8 activity did not change at any stage. The number of apoptotic cells increased at DII in the old CL. These results suggest an important role for this protease family during early events of luteolysis in the rat estrous cycle.
Phenotypes
Mutations
1 mutations
Species: mouse
Mutation name: caspase-2 gene disruption
type: null mutation fertility: fertile Comment: Mice with targeted inactivation of the caspase-2 gene, leading to a loss of both the long and short isoforms, are viable and appear to develop normally (Bergeron et al. 1998 ). Oocytes of caspase-2-deficient female mice are resistant to developmental and anticancer therapy-induced apoptosis (Bergeron et al. 1998 ).