Disease relevance of Casp9

• Administration of caspase-9 inhibitor also clears the exudate that normally fills the alveoli during Pcp and decreases lung inflammation [1].
• Furthermore, intracerebral ventricular infusion of the relatively specific caspase-9 inhibitor N-benzyloxycarbonyl-Leu-Glu-His-Asp-fluoro-methylketone before ischemia attenuated caspase-3-like activity and significantly enhanced neuronal survival in the CA1 sector [2].
• Cloning and characterization of rat caspase-9: implications for a role in mediating caspase-3 activation and hippocampal cell death after transient cerebral ischemia [2].
• Of significance is that the cloned promoter segments were activated by severe hypoxia, conditions inducing caspase-9 transcription [3].
• In the presence of cytochrome c and ATP, caspase-9 and -3 were activated, which initiated chromatin condensation and DNA cleavage in rat pheochromocytoma (PC12) nuclei [4].

High impact information on Casp9

• It induces purified mitochondria to release the apoptogenic proteins cytochrome c and caspase-9 [5].
• Inhibition of caspase 9, but not of caspases 3, 8, or 10, prevented hepatic stellate cell death [6].
• Caspase 9-dependent killing of hepatic stellate cells by activated Kupffer cells [6].
• We show that infection of human cells with the murine cytomegalovirus (MCMV) triggers the intrinsic apoptosis pathway involving caspase-9 activation [7].
• Indeed, cytochrome c was not released to the cytosol; Bax and caspase-9 and -3 were not involved; overexpressed Bcl-xL did not block the death; and the mitochondrial ultrastructure was not changed [8].

Chemical compound and disease context of Casp9

• Furthermore, melatonin treatment diminished cytochrome c release from mitochondria and reduced caspase 3 and caspase 9 activation induced by hyperhomocysteinemia [9].
• A tetracycline-regulated adenovirus encoding dominant-negative caspase-9 is regulated in rat brain and protects against neurotoxin-induced cell death in vitro, but not in vivo [10].
• Caspase-9 is a critical downstream effector molecule involved in apoptosis, a cell death process thought to be involved in the demise of dopamine (DA) neurons in the substantia nigra (SN) affected by Parkinson's disease (PD) [10].
• To study the mechanism underlying the anti-apoptotic effect of taurine, the interaction between taurine and Akt/caspase-9 pathway was examined using a simulated ischemia model with cultured rat neonatal cardiomyocytes sealed in closed flasks [11].
• The number of apoptotic (TUNEL, caspase-3, and caspase-9 positive) cells 1 day after ischemia was significantly more in the awake versus isoflurane group [12].

Biological context of Casp9

• Characterization of a novel isoform of caspase-9 that inhibits apoptosis [13].
• Our model is supported by reduced protease activity of casp-9-CTD preparations in vitro and by the lack of detectable processing of casp-9-CTD proenzyme or the induction of cell death following transfection into cells [13].
• In concert with these results, MUC1 attenuated (i) the loss of mitochondrial transmembrane potential, (ii) mitochondrial cytochrome c release, (iii) activation of caspase-9, and (iv) induction of apoptosis by the antimetabolite, 1-beta-d-arabinofuranosylcytosine [14].
• Both neuronal and non-neuronal cell types transfected with casp-9-CTD were resistant to death evoked by trophic factor deprivation or DNA damage [13].
• Here we have cloned the full-length cDNA of rat caspase-9 and have isolated promoter regions of this gene [3].

Anatomical context of Casp9

• The number of alveolar macrophages rebounds in caspase-9 inhibitor-treated Pcp animals [1].
• Immunoprecipitation experiments revealed that there was enhanced formation of Apaf-1/caspase-9 complex in the hippocampus 8 and 24 hours after ischemia [2].
• CONCLUSION: In Cy/Cy kidneys with ADPKD, there was an increase of the proform of caspase-9, an increase in cytochrome c release into the cytosol, and an increase in caspase-2 protein and activity demonstrating involvement of the intrinsic pathway [15].
• Depletion of polyamines prevented camptothecin-induced release of cytochrome c from mitochondria and decreased the activity of caspase-9 and caspase-3 [16].
• In rats with 0- to 20-day complete abdominal aorta ligation, the increases in IGF-II/IIR levels in the left ventricle were accompanied by hypertension as well as increases in caspase 9 activities and TUNEL-positive cardiac myocytes [17].

Associations of Casp9 with chemical compounds

• Depletion of recovered alveolar macrophages by intranasal administration of clodronate-containing liposomes in caspase-9 inhibitor-treated animals abrogates the effects of the inhibitor [1].
• The phosphatase inhibitors orthovanadate and okadaic acid prevented catalytic processing and activation of caspase-3 and digestion of Akt and partially inhibited cleavage of caspase-9 [4].
• The cytotoxic effect of Hcy was blocked by using small interfering RNA (siRNA)-mediated suppression of caspase-9 in MVEC [18].
• TMP was found to reduce the adriamycin-stimulated activities of caspase-3, caspase-8 and caspase-9, inhibit adriamycin-induced release of cytochrome C, and elevate the expression of Bcl-x (L) [19].
• Activation of caspase-9 and -3 during H2O2-induced apoptosis of PC12 cells independent of ceramide formation [20].

Physical interactions of Casp9

• RESULTS: Retinal detachment resulted in the time-dependent formation of the FAS-receptor/FAS-ligand complex that preceded the peak of caspase-9 activity and caspase-9/cytochrome c complex formation [21].

Regulatory relationships of Casp9

• Finally, we show that the caspase 8 inhibitor Ac-IETD-CHO was more effective at blocking seizure-induced cell death than the caspase 9 inhibitor Ac-LEHD-CHO [22].
• Suppressing the activation of caspase-9 inhibited the activation of caspase -3 and enhanced the cell viability and MP [18].
• Mitochondria play an important role in the regulation of apoptosis in mammalian cells because apoptotic signals induce mitochondria to release cytochrome c. The latter interacts with Apaf-1 to activate caspase-9, which in turn activates downstream caspase-3 [16].
• Correspondingly, expression of the mitochondrial proapoptotic factor Bax enhanced caspase 9 activation, plasma membrane blebbing, and drug-induced cytotoxicity [23].
• Conversely, overexpression of the mitochondrial antiapoptotic factor Bcl-2 blocked caspase 9 activation, leading to an inhibition of drug-induced plasma membrane permeability and blebbing, terminal deoxynucleotidyl transferase dUTP nick-end labeling positivity, PARP cleavage, Annexin V positivity, and drug-induced cell death [23].

Other interactions of Casp9

• In vitro induction of apoptosis can be inhibited by the caspase-9 inhibitor (Z-LEHD-FMK) but not by the inhibitor to caspase-8 or -10 [1].
• Apaf-1, Bcl-xL, cytochrome c, and caspase-9 form the critical elements for cerebral vascular protection by erythropoietin [24].
• In contrast, activation of caspase-1 and caspase-9 was not observed at any of the times studied after STS exposure [25].
• The expression of Bax, Bcl-2, caspase-3 and caspase-9 was regulated differently with aging between muscle types and in a manner not consistent with mitochondria-mediated apoptosis [26].
• Injury-induced cytochrome c-specific cleavage of caspase-9 followed by activation of caspase-3 in mature brain correlated with marked increases in Apaf-1 and caspase-3 mRNA and protein expression [27].

Analytical, diagnostic and therapeutic context of Casp9

• After 15-minute transient global ischemia, caspase-9 was overexpressed and proteolytically activated in the hippocampal CA1 neurons at 8 to 72 hours of reperfusion [2].
• Cell fractionation experiments revealed that sequestration of caspase-9 to cytoskeletal structures in 423-cells contributed to the observed impairment of apoptosome formation [28].
• On immunoblotting, there was an increase of the proform of both caspase-8 and caspase-9 in Cy/Cy kidneys [15].
• The increased cardiac IGF-II, IGF-IIR, caspase 9, and cellular apoptosis were also found in hypertensive rats with abdominal aorta ligation [17].
• Western blot analyses showed an increase in activities of calpain and caspase-12, upregulation of Bax:Bcl-2 ratio, release of cytochrome c from mitochondria, and increase in caspase-9 and caspase-3 activities during apoptosis [29].

References