Alternative titles; symbols
HGNC Approved Gene Symbol: CASP3
Cytogenetic location: 4q35.1 Genomic coordinates (GRCh38): 4:184,627,696-184,649,447 (from NCBI)
Cysteinyl aspartate-specific proteases, or caspases, such as CASP3, cleave substrates directly after an aspartic acid residue and play essential roles in programmed cell death. Caspases are synthesized in a dormant form with an N-terminal prodomain followed by a large subunit and a small subunit. Proteolytic processing releases the caspase large and small subunits, resulting in activation (summary by Parker et al., 2010).
Fernandes-Alnemri et al. (1994) cloned a gene encoding a 277-amino acid, 32-kD putative cysteine protease that they designated CPP32 from human Jurkat T cells. The CPP32 proenzyme undergoes proteolytic cleavage to produce 2 subunits, termed p20 and p11, which dimerize to form the active enzyme. CPP32 shares significant homology with mammalian ICE (CASP1; 147678), mouse Nedd2 (CASP2; 600639), and the Caenorhabditis elegans cell death protein Ced3. CPP32 showed highest expression in cell lines of lymphocytic origin.
By searching EST databases for sequences encoding the pentapeptide motif QACRG, which encompasses the catalytic cysteine of ICE, followed by screening an umbilical vein endothelial cell cDNA library, Tewari et al. (1995) cloned CASP3, which they called Yama after the Hindu god of death.
Huang et al. (2001) identified and cloned a short CASP3 splice variant, which they called CASP3s, from a human carcinoma cell line. CASP3s appeared to result from a deletion of exon 6 that shifts the reading frame in the C terminus, leading to an altered amino acid sequence and a truncated polypeptide. The deduced 182-amino acid protein contains the complete N terminus but is missing 95 residues at the C terminus, including the conserved QACRG sequence at the catalytic site. PCR analysis of 16 human tissues revealed expression of full-length CASP3, as well as CASP3s at somewhat lower levels, in all tissues tested. Western blot analysis of 3 cell lines revealed the prominent CASP3 band at 32 kD and CASP3s at 20 kD. Several human cancer cell lines showed coexpression of both variants at the mRNA and protein levels. Overexpression of the catalytically inactive CASP3s by human kidney cells offered some resistance to inducers of apoptosis, and CASP3s accumulation could be enhanced with addition of proteasome inhibitors.
Fernandes-Alnemri et al. (1994) found that overexpression of CPP32 in insect cells induced apoptosis. Coexpression of the 2 CPP32 subunits in insect cells also resulted in apoptosis.
An early event that occurs concomitantly with the onset of apoptosis is the proteolytic breakdown of poly(ADP-ribose) polymerase (PARP; 173870) by a protease with properties resembling those of caspase-1. The resulting cleavage, between asp216 and gly217, separates the N-terminal DNA-nick sensor of PARP from its C-terminal catalytic domain. To identify the enzyme responsible for PARP inactivation in mammalian cells during apoptosis, Nicholson et al. (1995) purified the activity to homogeneity from cultured human cells of malignant cell lines with relatively high levels of this proteolytic activity. This enzyme, which they named apopain, was composed of 2 subunits of relative molecular masses 17 and 12 kD derived from a common proenzyme identified as CPP32. Nicholson et al. (1995) developed a potent peptide aldehyde inhibitor and showed that it prevented apoptotic events in vitro, suggesting that apopain/CPP32 is important for the initiation of apoptotic cell death.
Tewari et al. (1995) showed that purified human ICE cleaved the Yama proenzyme into a proteolytically active form and that activated Yama cleaved PARP into the 85-kD apoptotic form. They also found that poxvirus crimA interacted directly with activated Yama, but not Yama proenzyme, and inhibited Yama-dependent PARP activation.
Fernandes-Alnemri et al. (1996) showed that CPP32 could be cleaved from its proenzyme form to its 2 subunits by either granzyme B (GZMB; 123910) or by a related cysteine protease, MCH4 (601762).
Quan et al. (1996) independently showed that granzyme B proteolytically activated human Yama.
Apoptosis of human endothelial cells after growth factor deprivation is associated with rapid and dramatic upregulation of cyclin A-associated cyclin-dependent kinase-2 (CDK2; 116953) activity. Levkau et al. (1998) showed that in apoptotic cells the carboxyl termini of the CDK inhibitors CDKN1A (116899) and CDKN1B (600778) are truncated by specific cleavage. The enzyme involved in this cleavage is CASP3 and/or a CASP3-like caspase. After cleavage, CDKN1A loses its nuclear localization sequence and exits the nucleus. Cleavage of CDKN1A and CDKN1B resulted in a substantial reduction in their association with nuclear cyclin-CDK2 complexes, leading to a dramatic induction of CDK2 activity. Dominant-negative CDK2, as well as a mutant CDKN1A resistant to caspase cleavage, partially suppressed apoptosis. These data suggested that CDK2 activation, through caspase-mediated cleavage of CDK inhibitors, may be instrumental in the execution of apoptosis following caspase activation.
Mannick et al. (1999) demonstrated that caspase-3 zymogens are S-nitrosylated on their catalytic-site cysteine in unstimulated human cell lines and denitrosylated upon activation of the Fas (134637) apoptotic pathway. Decreased caspase-3 S-nitrosylation was associated with an increase in intracellular caspase activity. Fas therefore activates caspase-3 not only by inducing the cleavage of the caspase zymogen to its active subunits, but also by stimulating the denitrosylation of its active-site thiol. Protein S-nitrosylation/denitrosylation can thus serve as a regulatory process in signal transduction pathways. Mannick et al. (1999) suggested that nitric oxide-related activity helps maintain caspase-3 zymogen in an inactive form and that this regulation is achieved by S-nitrosylation of the catalytic-site cysteine.
Gervais et al. (1999) found that the amyloid-beta 4A precursor protein (APP; 104760) is directly and efficiently cleaved by caspases during apoptosis, resulting in elevated amyloid-beta peptide formation. The predominant site of caspase-mediated proteolysis is within the cytoplasmic tail of APP, and cleavage at this site occurs in hippocampal neurons in vivo following acute excitotoxic or ischemic brain injury. Caspase-3 is the predominant caspase involved in APP cleavage, consistent with its marked elevation in dying neurons of Alzheimer disease (104300) brains and colocalization of its APP cleavage product with amyloid-beta in senile plaques. Caspases thus appear to play a dual role in proteolytic processing of APP and the resulting propensity for amyloid-beta peptide formation, as well as in the ultimate apoptotic death of neurons in Alzheimer disease.
Huntington disease (143100) is a neurodegenerative disorder caused by trinucleotide repeat expansion mutations, which result in extended polyglutamine tracts in the huntingtin protein (613004). Transgenic mice expressing N-terminal mutant huntingtin show intranuclear huntingtin accumulation and develop progressive neurologic symptoms. Inhibiting caspase-1 (147678) can prolong the survival of these HD mice. Li et al. (2000) reported that intranuclear huntingtin induces the activation of caspase-3 and the release of cytochrome c (123970) from mitochondria in cultured cells. As a result, cells expressing intranuclear huntingtin underwent apoptosis. Intranuclear huntingtin increased the expression of caspase-1, which may in turn activate caspase-3 and trigger apoptosis. The authors proposed that the increased level of caspase-1 induced by intranuclear huntingtin may contribute to HD-associated cell death.
The cellular alterations associated with skeletal muscle differentiation share a high degree of similarity with key phenotypic changes usually ascribed to apoptosis. For example, actin fiber disassembly/reorganization is a conserved feature of both apoptosis and differentiating myoblasts, and the conserved muscle contractile protein myosin light chain kinase (MYLK; 600922) is required for the apoptotic feature of membrane blebbing. As such, these observations suggest that the induction of differentiation and apoptosis in the myogenic lineage may use overlapping cellular mechanisms. Fernando et al. (2002) reported that skeletal muscle differentiation depends on the activity of the key apoptotic protease caspase-3. Peptide inhibition of caspase-3 activity or homozygous deletion of caspase-3 leads to dramatic reduction in both myotube/myofiber formation and expression of muscle-specific proteins. Fernando et al. (2002) identified mammalian sterile 20-like kinase (MST1; 604965) as a crucial caspase-3 effector in this cellular process. MST1 is cleavage-activated by caspase-3, and restoration of this truncated kinase in caspase-3-null myoblasts restores the differentiation phenotype. Taken together, these results confirm a unique and unanticipated role for a caspase-3-mediated signal cascade in the promotion of myogenesis.
Phosphatidylserine (PS) is sequestered in the inner membrane leaflet through the activity of aminophospholipid translocase (see 609542). Phagocytosis of erythrocytes is largely dependent upon the presence of PS on the outer membrane leaflet. Mandal et al. (2002) found that pro-CASP3 was expressed in mature anucleated human erythrocytes. CASP3 was activated following oxidative stress, concomitant with PS externalization and erythrocyte phagocytosis. Pharmacologic inhibition of CASP3 partly blocked PS externalization and erythrocyte phagocytosis. Mandal et al. (2002) concluded that activated CASP3 blocks PS translocase activity, promoting loss of PS asymmetric distribution and phagocytosis of erythrocytes.
Jiang et al. (2003) identified a small molecule, alpha-(trichloromethyl)-4-pyridineethanol (PETCM), as an activator of caspase-3 by stimulation of apoptosome formation.
Okuyama et al. (2004) found that pure keratinocytes cultured from embryonic day-15.5 mouse embryos committed irreversibly to differentiation much earlier than those cultured from newborn mice. Notch signaling, which promotes keratinocyte differentiation, was upregulated in embryonic keratinocytes and epidermis, and elevated caspase-3 expression, which the authors identified as a target for Notch1 (190198) transcriptional activation, accounted in part for the high commitment of embryonic keratinocytes to terminal differentiation.
Chang et al. (2003) examined cardiac SRF (600589) protein levels from 23 patients with end-stage heart failure, 10 of whom were supported by left ventricular assist devices (LVAD), and 7 normal hearts. Full-length SRF was markedly reduced and processed into 55- and 32-kD subfragments in the 13 unsupported failing hearts. SRF was intact in normal samples, whereas samples from the hearts of the 10 LVAD patients showed minimal SRF fragmentation. Specific antibodies to N- and C-terminal SRF sequences and site-directed mutagenesis revealed 2 alternative caspase-3 cleavage sites. Expression of the 32-kD N-terminal SRF fragment in myogenic cells inhibited the transcriptional activity of alpha-actin (102610) gene promoters by 50 to 60%. Chang et al. (2003) concluded that caspase-3 activation in heart failure sequentially cleaves SRF and generates a truncated SRF that appears to function as a dominant-negative transcription factor. They suggested that caspase-3 activation may be reversible in the failing heart with ventricular unloading.
Miura et al. (2004) reported delayed ossification and decreased bone mineral density of Casp3-deficient mice due to attenuated osteogenic differentiation of bone marrow stromal cells. The mechanism for the impaired differentiation involved overactivation of the transforming growth factor beta-1 (TGFB1; 190180)/SMAD2 (601366) signaling pathway, ultimately resulting in increased replicative senescence. CASP3 inhibitor caused accelerated bone loss in ovariectomized mice, a model for postmenopausal osteoporosis. Miura et al. (2004) concluded that the CASP3 influence on bone mineral density should be considered in any in vivo application of CASP3 inhibitors to the treatment of human disease.
Ribeil et al. (2007) demonstrated that during erythroid differentiation but not apoptosis, the chaperone protein Hsp70 (140550) protects GATA1 (305371) from caspase-mediated proteolysis. At the onset of caspase activation, Hsp70 colocalizes and interacts with GATA1 in the nucleus of erythroid precursors undergoing terminal differentiation. In contrast, erythropoietin starvation induces the nuclear export of Hsp70 and the cleavage of GATA1. In an in vitro assay, Hsp70 protected GATA1 from CASP3-mediated proteolysis through its peptide-binding domain. Ribeil et al. (2007) used RNA-mediated interference to decrease the Hsp70 content of erythroid precursors cultured in the presence of erythropoietin. This led to GATA1 cleavage, a decrease in hemoglobin content, downregulation of the expression of the antiapoptotic protein Bcl-XL (see 600039), and cell death by apoptosis. These effects were abrogated by the transduction of a caspase-resistant GATA1 mutant. Thus, Ribeil et al. (2007) concluded that in erythroid precursors undergoing terminal differentiation, Hsp70 prevents active CASP3 from cleaving GATA1 and inducing apoptosis.
Nitric oxide (see 163731) acts substantially in cellular signal transduction through stimulus-coupled S-nitrosylation of cysteine residues. Benhar et al. (2008) searched for denitrosylase activities, and focused on caspase-3, an exemplar of stimulus-dependent denitrosylation, and identified thioredoxin (see 187700) and thioredoxin reductase (see 601112) in a biochemical screen. In resting human lymphocytes, thioredoxin-1 actively denitrosylated cytosolic caspase-3 and thereby maintained a low steady-state amount of S-nitrosylation. Upon stimulation of Fas, thioredoxin-2 (609063) mediated denitrosylation of mitochondria-associated caspase-3, a process required for caspase-3 activation, and promoted apoptosis. Inhibition of thioredoxin-thioredoxin reductases enabled identification of additional substrates subject to endogenous S-nitrosylation. These substrates included caspase-9 (CASP9; 602234) and protein tyrosine phosphatase-1B (176885). Thus, Benhar et al. (2008) concluded that specific enzymatic mechanisms may regulate basal and stimulus-induced denitrosylation in mammalian cells.
Srikanth et al. (2010) found that during infection of intestinal epithelial cells with the Salmonella serovar Typhimurium, the effector Salmonella invasion protein A (SipA) is responsible for the early activation of caspase-3, an enzyme that is required for SipA cleavage at a specific recognition motif that divides the protein into its 2 functional domains and activates SipA in a manner necessary for pathogenicity. Other caspase-3 cleavage sites identified in S. Typhimurium appeared to be restricted to secreted effector proteins, which indicated that this may be a general strategy used by this pathogen for processing of its secreted effectors.
Using rat and mouse hippocampal brain slices, Li et al. (2010) showed that the Casp9-Casp3 mitochondrial signaling pathway used to induce apoptosis also has a role in neuronal plasticity. Activation of Casp3 was required for long-term synaptic depression and AMPA receptor (see 138248) internalization, but not for long-term potentiation. Long-term depression and AMPA receptor internalization were blocked by peptide inhibitors of Casp3 and Casp9. In hippocampal slices from Casp3 -/- mice, long-term depression was abolished, whereas long-term potentiation remained intact. Long-term depression was also abolished by overexpression of the antiapoptotic proteins Xiap (300079) or Bclxl, and by a mutant Atk1 (164730) protein that was resistant to Casp3 proteolysis. NMDA receptor (see 138249) stimulation that induced long-term depression activated Casp3 in dendrites without causing cell death. Li et al. (2010) concluded that CASP3 has a nonapoptotic role in AMPA receptor internalization and synaptic plasticity.
Burguillos et al. (2011) showed that the orderly activation of caspase-8 (601763) and caspase-3/7 (601761), known executioners of apoptotic cell death, regulate microglia activation through a protein kinase C-delta (PRKCD; 176977)-dependent pathway. Burguillos et al. (2011) found that stimulation of microglia with various inflammogens activates caspase-8 and caspase-3/7 in microglia without triggering cell death in vitro and in vivo. Knockdown or chemical inhibition of each of these caspases hindered microglia activation and consequently, reduced neurotoxicity. The authors observed that these caspases are activated in microglia in the ventral mesencephalon of Parkinson disease (168600) and the frontal cortex of individuals with Alzheimer disease (104300). Burguillos et al. (2011) concluded that caspase-8 and caspase-3/7 are involved in regulating microglia activation, and suggested that inhibition of these caspases could be neuroprotective by targeting the microglia rather than the neurons themselves.
Murthy et al. (2014) showed that amino acids 296 to 299 of ATG16L1 constitute a caspase cleavage motif and that the T300A variant (610767.0001) (T316A in mice) significantly increases ATG16L1 sensitization to CASP3-mediated processing. Murthy et al. (2014) observed that death receptor activation or starvation-induced metabolic stress in human and murine macrophages increased degradation of the T300A or T316A variants of ATG16L1, respectively, resulting in diminished autophagy. Knockin mice harboring the T316A variant showed defective clearance of the ileal pathogen Yersinia enterocolitica and an elevated inflammatory cytokine response. In turn, deletion of Casp3 or elimination of the caspase cleavage site by site-directed mutagenesis rescued starvation-induced autophagy and pathogen clearance, respectively. Murthy et al. (2014) concluded that these findings demonstrated that CASP3 activation in the presence of a common risk allele leads to accelerated degradation of ATG16L1, placing cellular stress, apoptotic stimuli, and impaired autophagy in a unified pathway that predisposes to Crohn disease (611081).
Using mouse and human cells, Rogers et al. (2017) found that CASP3 cleaved GSDME (608798) after asp270 to generate a necrotic N-terminal fragment that targeted itself to the plasma membrane to induce secondary necrosis/pyroptosis. Cells expressing GSDME progressed to secondary necrosis when stimulated with apoptotic triggers, such as etoposide or vesicular stomatitis virus, but disassembled into small apoptotic bodies when GSDME was deleted. Rogers et al. (2017) concluded that GSDME is a central molecule that regulates apoptotic cell disassembly and progression to secondary necrosis.
Independently, Wang et al. (2017) found that CASP3 cleaved human GSDME following asp270 in vitro and in cell lines, and that the N-terminal fragment of GSDME changed the cellular response to TNF (191160) or chemotherapeutic agents from apoptosis to pyroptosis. Human cell lines that lacked GSDME expression did not show pyroptotic response to TNF or chemotherapeutic agents. Mutation of asp267 or asp270 in the CASP3 recognition motif of GSDME, knockout of GSDME expression, or knockout or inhibition of CASP3 abrogated the pyroptotic response to TNF or chemotherapeutic agents. Liposome experiments suggested that pyroptosis involved binding of the N-terminal domain of GSDME to phosphatidylinositol-4,5-bisphosphate, formation of pores, and loss of liposome contents. Compared with wildtype, Gsdme -/- mice were refractory to cisplatin- or bleomycin-induced injury of gastrointestinal tissues, spleen, and lung. Wang et al. (2017) concluded that CASP3 cleaves and activates GSDME, causing pyroptosis, and that the expression level of GSDME determines the form of cell death in CASP3-activated cells.
Nasir et al. (1997) used fluorescence in situ hybridization of a genomic clone isolated from a P1 library to map CPP32 to the tip of the long arm of human chromosome 4. Its localization was refined against a YAC contig from this region spanning at least 2 Mb. CPP32 mapped between the KLKB1 (229000) and F11 (264900) loci on the one side and D4S254 on the other. It was contained within the same 240-kb YAC as the FACL2 gene (152425).
Tiso et al. (1996) used radiation hybrid mapping to localize the CPP32 gene to human chromosome 4q33-q35.1. They observed that each of 4 CASP family genes mapped colocalizes with an autosomal dominant malformative disease. They suggested William syndrome (194050) as a candidate genetic disease at the 4q33-q35 locus.
Associations Pending Confirmation
Kawasaki disease (KD; 611775) is an acute vasculitis syndrome which predominantly affects small- and medium-sized arteries of infants and children. Onouchi et al. (2010) reported that multiple variants in CASP3 that are in linkage disequilibrium conferred susceptibility to KD in both Japanese and United States subjects of European ancestry. A G-to-A substitution of a commonly associated SNP located in the 5-prime untranslated region of CASP3 (rs72689236) abolished binding of nuclear factor of activated T cells (NFATC1; 600489) to the DNA sequence surrounding the SNP. The authors suggested that altered CASP3 expression in immune effector cells influences susceptibility to KD.
Somatic Mutations
Failure of apoptosis is one of the hallmarks of cancer. To explore the possibility that genetic alterations in the CASP3 gene might be involved in the development of human tumors, Soung et al. (2004) analyzed the entire coding region and all splice sites of the gene for somatic mutations in a series of 944 human tumors. Overall, they detected 14 somatic mutations: 4 of 98 colon carcinomas (4.1%), 4 of 181 nonsmall cell lung cancers (2.2%), 2 of 129 non-Hodgkin lymphomas (1.6%), 2 of 165 stomach carcinomas (1.2%), 1 of 80 hepatocellular carcinomas (1.3%), and 1 of 28 multiple myelomas (3.6%). No somatic mutations were found in 76 breast carcinomas, 45 acute leukemias, 12 medulloblastomas, 15 Wilms tumors, 12 renal cell carcinomas, 40 esophagus carcinomas, 33 urinary bladder carcinomas, and 33 laryngeal carcinomas.
Human evolution is characterized by a dramatic increase in brain size and complexity. To probe its genetic basis, Dorus et al. (2004) examined the evolution of genes involved in diverse aspects of nervous system biology. These genes, including CASP3, displayed significantly higher rates of protein evolution in primates than in rodents. This trend was most pronounced for the subset of genes implicated in nervous system development. Moreover, within primates, the acceleration of protein evolution was most prominent in the lineage leading from ancestral primates to humans. Dorus et al. (2004) concluded that the phenotypic evolution of the human nervous system has a salient molecular correlate, i.e., accelerated evolution of the underlying genes, particularly those linked to nervous system development.
To analyze the function of CPP32 in vivo, Kuida et al. (1996) generated CPP32-deficient mice by homologous recombination. These mice, born at a frequency lower than expected by mendelian genetics, were smaller than their littermates and died at 1 to 3 weeks of age. Although their thymocytes retained normal susceptibility to various apoptotic stimuli, brain development in CPP32-deficient mice was profoundly affected, and discernible by embryonic day 12, resulting in a variety of hypoplasias and disorganized cell deployment. These supernumerary cells were postmitotic and terminally differentiated by the postnatal stage. Pyknotic clusters at sites of major morphogenetic change during normal brain development were not observed in the mutant embryos, indicating increased apoptosis in the absence of CPP32. Thus, CPP32 was shown by Kuida et al. (1996) to play a critical role during morphogenetic cell death in the mammalian brain.
Woo et al. (1998) generated mice, embryonic stem (ES) cells, and mouse embryonic fibroblasts (MEFs) lacking exon 3 of Casp3. The phenotype of the mice was consistent with that observed by Kuida et al. (1996). However, Woo et al. (1998) observed that in ES cells, Casp3 was necessary for efficient apoptosis following ultraviolet but not gamma irradiation. On the other hand, tumor necrosis factor (TNF; 191160) induced normal apoptosis in Casp3 -/- thymocytes but defective apoptosis in transformed MEFs. In addition, apoptotic events such as chromatin condensation and DNA degradation were not displayed in all cell types; however, other hallmarks of apoptosis were displayed by these cells. Woo et al. (1998) concluded that the requirement for CASP3 in apoptosis is tissue-specific and even stimulus-specific within the same cell type, underscoring the complexity of apoptotic control in mammalian systems as well as the potential for selective blocking of cell death.
Woo et al. (2003) reported that mice deficient in Casp3 had increased numbers of splenic B cells showing both normal apoptosis and enhanced proliferation in vivo and hyperproliferation after mitogenic stimulation in vitro. However, in the absence of both Casp3 and Cdkn1a, the hyperproliferation of Casp3 -/- B cells was abolished. Woo et al. (2003) concluded that hyperproliferation of T cells in Casp3-deficient mice is due to impaired apoptosis, whereas hyperproliferation in B cells is due to increased cell cycling. The results indicated that Casp3 acts as a negative regulator of cell cycle progression in B lymphocytes.
B-cell apoptosis has been implicated in the initiation of type 1 diabetes mellitus (T1D; 222100) through antigen cross-presentation mechanisms that lead to B cell-specific T-cell activation. Liadis et al. (2005) found that Casp3 -/- mice were protected from developing diabetes in a streptozotocin autoimmune diabetes model. Lymphocyte infiltration of pancreatic islets was completely absent in Casp3 -/- mice. Further studies showed that Casp3-mediated B-cell apoptosis was a requisite step for T-cell priming and initiation of type 1 diabetes.
Zeiss et al. (2004) evaluated the impact of caspase-3 ablation on photoreceptor degeneration and studied its role in postnatal retinal development in the rd mouse. They found that Casp3-deficient mice displayed marginal microphthalmia, peripapillary retinal dysplasia, delayed regression of vitreal vasculature, and retarded apoptotic kinetics of the inner nuclear layer. Although ablation of caspase-3 provided transient photoreceptor protection, rod death proceeded. Zeiss et al. (2004) concluded that in vivo, caspase-3 is not critical for rod photoreceptor development, nor does it play a significant role in mediating pathologic rod death. The temporal nature of apoptotic retardation in the absence of caspase-3 implied the presence of caspase-independent mechanisms of developmental and pathologic cell death.
Tao et al. (2005) had previously shown that the amount of Casp3 was increased in a rat model of polycystic kidney disease (PKD; 173900). They found that the caspase inhibitor IDN-8050 reduced kidney enlargement by 44% and cyst volume by 29% in heterozygous (Cy/+) mutant rats with PKD. In Cy/+ rats, caspase inhibition led to reduced blood urea nitrogen and reduced numbers of Pcna (176740)-positive tubular cells and apoptotic tubular cells. Western blot analysis showed that the reduced amount of active Casp3 following IDN-8050 treatment was associated with reduced cyst formation and disease progression.
Lakhani et al. (2006) generated mice doubly deficient for Casp3 and Casp7, which died immediately after birth with defects in cardiac development. Fibroblasts lacking both enzymes were highly resistant to both mitochondrial and death receptor-mediated apoptosis, displayed preservation of mitochondrial membrane potential, and had defective nuclear translocation of apoptosis-inducing factor (AIF; 300169). Furthermore, the early apoptotic events of Bax (600040) translocation and cytochrome c (123970) release were also delayed. Lakhani et al. (2006) concluded that caspases 3 and 7 are critical mediators of mitochondrial events of apoptosis.
Using a clickbox test and auditory brainstem response analysis, Parker et al. (2010) found that the 'melody' line of homozygous mutant mice, which was generated in an N-ethyl-N-nitrosourea screen, exhibited profound deafness. They identified the melody mutation as a cys163-to-ser substitution in the catalytic site of Casp3. Scanning electron microscopy and histologic analysis of homozygous melody mice revealed disorganized sensory hair cells, hair cell loss, and degeneration of spiral ganglion cells, with a gradient of severity from apical to basal turns. Melody heterozygotes also showed evidence of loss of spiral ganglion neurons, suggesting dominant-negative effects.
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