Disease relevance of Casp7

• In addition, mutant neurons showed no evidence of compensatory activation by caspase-6 or caspase-7 after ischemia [1].
• In the WEHI-231 B cell lymphoma model, anti-IgM crosslinking triggers activation of caspase-7 independently of caspase-8, followed by apoptosis [2].
• Western blot analysis confirmed that in cardiomyopathies no cleavage of caspase-3 and caspase-7 occurred [3].

High impact information on Casp7

• Moreover, we demonstrate that the mammalian IAP c-IAP1 interacts with caspase-7 in an exclusively IBM-dependent, but active site pocket-independent, manner that is mechanistically similar to DIAP1 [4].
• Here we report that caspase-7 activation induced by BCR crosslinking is independent of caspase-8 and cytochrome c translocation from mitochondria to the cytosol, as well as of mitochondrial depolarization [2].
• We demonstrate that calpain specifically triggers activation and processing of caspase-7 both in vitro and in vivo, and that both processes are inhibited by calpain inhibitors [2].
• Treatment with Let, Tam, or E2W resulted in a dose- and time-dependent increase in active caspase-7 and up-regulation of p53 and p21 protein [5].
• No apoptosis was observed in the cells where caspase-7 did not undergo autocatalytic activation [6].

Biological context of Casp7

• Neither of the inhibitors prevented Mch3 processing; however, z-VAD-fmk prevented proteolysis of the p32 subunit, suggesting that further processing of this subunit is associated with apoptosis [7].
• On the basis of sequence homology, the caspases can be divided into three subfamilies: first, mCASP-1, mCASP-11 and mCASP-12; second, mCASP-2; third, mCASP-3, mCASP-6 and mCASP-7 [8].
• Finally, we also show that teratogen-induced activation of caspase-6 and caspase-7 are blocked in the heart, a tissue resistant to teratogen-induced cell death [9].
• Together, our findings demonstrate for the first time a strong correlation between caspase-7 activity, normal brain development, and apoptotic DNA fragmentation in Casp3-/- mice [10].
• Caspase-7 expanded function and intrinsic expression level underlies strain-specific brain phenotype of caspase-3-null mice [10].

Anatomical context of Casp7

• In splenic B cells, Mch3 is also specifically proteolyzed ex vivo after induction of apoptosis by BCR cross-linking, demonstrating the specific involvement of caspase-7/Mch3 in apoptosis induced in B cell tolerance [7].
• Active caspase-3 is confined primarily to the cytosol, whereas active caspase-7 is associated almost exclusively with the mitochondrial and microsomal fractions [11].
• The addition of zinc to transfectants containing MAIR cDNA as part of a heavy metal-inducible vector caused apoptosis of the cells characterized by cell fragmentation; a reduction in mitochondrial membrane potential; activation of caspase-7, -8, and -9, but not caspase-3; and DNA degradation [12].
• In an attempt to elucidate the specific role of caspase-7 we generated a chicken DT40 cell line in which both alleles of the gene were disrupted [13].
• Translocation and activation of caspase-7 to the endoplasmic reticulum correlates with the proteolytic cleavage of the endoplasmic reticular-specific substrate, sterol regulatory element-binding protein 1 [11].

Associations of Casp7 with chemical compounds

• Mouse Casp7 encodes a putative 340-amino-acid polypeptide that contains all the known conserved residues required for protease function, including the QACRG sequence, aspartic acid residues for internal cleavage sites, and the residues required for substrate binding [14].
• Here, we describe the cloning of mouse and human Casp7, another member of this family of cysteine proteases [14].
• Liver damage, induction of apoptosis, activation and translocation of caspase-7, and proteolysis of sterol regulatory element-binding protein 1 are all blocked by the caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp fluoromethyl ketone (Z-VAD. fmk) [11].
• Two CPP32-like proteases, CPP32 and Mch-3, are expressed in untreated and retinoic acid-treated P19 EC cells [15].
• Furthermore, addition of spermine could repress the BCR-mediated apoptosis by attenuating the mitochondrial membrane potential (Deltapsim) loss and activation of caspase-7 induced by BCR signaling [16].

Enzymatic interactions of Casp7

• Of note, caspase 3 was shown to cleave TcapQ647 with a kcat 7-fold greater than caspase 7 and 16-fold greater than caspase 6 [17].
• These results collectively suggest that caspase-3 or caspase-7 cleaves calnexin, whose cleaved product leads to the attenuation of apoptosis [18].

Regulatory relationships of Casp7

• In contrast, caspase-7 could be activated by addition of recombinant caspase-3 but only minimally by recombinant caspase-9 [9].

Other interactions of Casp7

• Bcl-2 overexpression prevented anti- micro induction of CPP32-like activity and apoptosis, and blocked further processing of the Mch3 p32 subunit [7].
• Histopathological changes in lungs of mice administered benzo(a)pyrene (BP) were followed serially and correlated with the expression of Cox-2, caspase-3 and caspase-7, which play key roles in histopathogenesis of neoplasia [19].
• We have found increased levels of apoptosis as well as increased caspase-3 and caspase-7 gene expression in the intestines of GC-C-deficient Apc(Min/+) mice compared with Apc(Min/+) mice [20].
• We did not detect the presence of caspase-7 in the ER fraction at the period of caspase-12 cleavage [21].
• Elk-3 and Caspase-7 were not expressed in vitro in cultured cell lines, suggesting that their expression was induced by the tumor microenvironment [22].

Analytical, diagnostic and therapeutic context of Casp7

• Northern blot analysis demonstrated that a 2.6-kb Casp7 mRNA was expressed in various tissues except brain [14].
• RESULTS: Western blot analyses show that these three teratogens, HS, 4CP, and ST, induce the activation of procaspase-6 (appearance of the 13 kDa subunit, p13) and caspase-7 (appearance of the 19 kDa subunit, p19) in day 9 mouse embryos [9].
• The data presented here show, by fluorescence microscopic and immunoblotting analyses, that a prodomain of caspase-7 inhibits its nuclear translocation and apoptosis-inducing activity [23].
• I/R-induced renal apoptosis was only present in tubular epithelial cells with evident disruption of brush border as assessed by immunohistochemistry for active caspase-7 and filamentous actin, respectively [24].
• CONCLUSION: Rz333 can site-specific cleave mouse caspase-7 mRNA, and it shows a potential for gene therapy of apoptosis-related diseases by down-regulating gene expression of caspase-7 [25].

References