Disease relevance of Apaf1

• Differential expression of apoptotic protease-activating factor-1 and caspase-3 genes and susceptibility to apoptosis during brain development and after traumatic brain injury [1].
• Chronic hyperglycemia exacerbated baseline and MG-induced apoptosis that corresponded to exaggerated loss of cytosolic and mitochondrial redox balance, impaired glucose 6-phosphate dehydrogenase (G6PD) activity, and enhanced basal expression of apoptosis protease activator factor-1 (Apaf-1) [2].
• Immunoprecipitation experiments revealed that there was enhanced formation of Apaf-1/caspase-9 complex in the hippocampus 8 and 24 hours after ischemia [3].
• Apaf1-deficient mice exhibited reduced apoptosis in the brain and striking craniofacial abnormalities with hyperproliferation of neuronal cells [4].
• Transforming growth factor-beta(1) induces apoptosis in rat FaO hepatoma cells via cytochrome c release and oligomerization of Apaf-1 to form a approximately 700-kd apoptosome caspase-processing complex [5].

High impact information on Apaf1

• Caspase-3 activation in vitro can be triggered by upstream events, leading to the release of cytochrome c from the mitochondria and the subsequent transactivation of procaspase-9 by Apaf-1 [6].
• Because a complete deficiency in Apaf-1 usually results in perinatal lethality and fog/fog mice more readily survive into adulthood, these mutants serve as a valuable model with which apoptotic cell death can be studied in vivo [7].
• Altering cellular GSH with ethacrynic acid or N-acetylcysteine, respectively, exacerbated or protected against dPC12 apoptosis. dPC12 apoptosis was mediated by caspase-9 and -3 activation and apoptosis protease activator protein-1 (Apaf-1) expression [8].
• These results show that nPC12 transition to dPC12 cells afforded protection against oxidative challenge due to maintenance of reduced GSH/GSSG and decreased Apaf-1 expression [8].
• Apaf-1 was found to interact with cytochrome c within the injured hippocampus 0-24 h following seizures by co-immunoprecipitation analysis and immunohistochemistry demonstrated Apaf-1/cytochrome c co-localization [9].

Biological context of Apaf1

• Endothelial cell injury was evaluated by trypan blue, DNA fragmentation, membrane phosphatidylserine exposure, apoptotic protease-activating factor-1 (Apaf-1), and Bcl-XL expression, mitochondrial membrane potential, cytochrome c release, and cysteine protease activity [10].
• A similar decline in apoptotic susceptibility associated with downregulation of Apaf-1 expression as a function of developmental age was also found in cultured primary rat cortical neurons [1].

Anatomical context of Apaf1

• Exogenous EPO maintains both genomic DNA integrity and cellular membrane asymmetry through parallel pathways that prevent the induction of Apaf-1 and preserve mitochondrial membrane potential in conjunction with enhanced Bcl-XL expression [10].
• We show herein that 2 h after triggering apoptosis with rotenone, Apaf-1 redistributed to the proximity of mitochondria [11].
• In adult brain, Apaf-1 activity was scarcely detected, while the tissue retained low but significant amounts of procaspase 9 (16% of that in the fetal tissue) and a pro-DEVDase (3.4%) [12].
• We conclude that (i) c-Jun and Apaf-1 play major roles in the apoptotic cascade of RGC and may represent useful targets for antiapoptotic strategies in RGC in vivo, and (ii) injection of siRNAs into the optic nerve stump is a new method to down-regulate target genes specifically in RGC [13].
• Furthermore, we found colocalization of activated caspase-3 with apoptotic protease-activating factor-1 (Apaf-1) in apoptotic germ cells, thus indicating the importance of the intrinsic mitochondrial pathway in TGF-beta-induced apoptosis [14].

Associations of Apaf1 with chemical compounds

• Reduced glucose availability in hyperglycemia-adapted nPC12 cells induced by acute lowering of glucose or by dehydroepiandrosterone (DHEA, G6PD inhibitor) further enhanced MG-induced apoptosis in association with greater cytosolic and mitochondrial redox and G6PD impairment and elevated basal Apaf-1 expression [2].
• Taurine inhibits apoptosis by preventing formation of the Apaf-1/caspase-9 apoptosome [15].
• Up-regulation of bcl-2, inhibitor of Apaf-1/caspase-9/caspase-2 cascade of apoptosis, may be related to the fact that no morphological apoptotic change was induced after dosing of 20 mg/kg DEHP [16].
• Inhibition of CXCR 4 by AMD 3100 abrogates the effect of gp120 on both p53 and Apaf-1 [17].

Regulatory relationships of Apaf1

• 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 [18].

Other interactions of Apaf1

• Consistent with the modulation of Apaf-1 and the release of cytochrome c, EPO also inhibits the activation of caspase-9 and caspase-3-like activities [10].
• These results suggest that differential expression of Apaf-1 and caspase-3 genes may underlie regulation of apoptotic susceptibility during brain development, as well as after acute injury to mature brain, through the intrinsic pathway of caspase activation [1].
• Normally, caspases exist in cells as inactive pro-enzymes and can be activated by 2 distinct mechanisms: the FADD/caspase 8 cascade, and the Apaf-1/caspase 9 cascade [19].
• We found that gp120 stimulates p53 activity and induces expression of the p53 pro-apoptotic target Apaf-1 in cultured neurons [17].
• The E2F-1/p53/Apaf-1 pathway appears to be targeted by UDCA [20].

Analytical, diagnostic and therapeutic context of Apaf1

• The expression of apoptotic proteins was quantified by Western blot analysis, and the specific interaction between Hsp70 and apoptotic protease activating factor 1 (Apaf-1) was determined by coimmunoprecipitation [21].
• RT-PCR and immunoblotting confirmed a decrease in Apaf-1 [20].

References