Search results for APAF1

Showing 21 results out of 42

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Species

Types

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Protein (4 results from a total of 4)

Identifier: R-HSA-50099
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: APAF1: O14727
Identifier: R-HSA-6801301
Species: Homo sapiens
Compartment: ficolin-1-rich granule lumen
Primary external reference: UniProt: APAF1: O14727
Identifier: R-HSA-6806465
Species: Homo sapiens
Compartment: extracellular region
Primary external reference: UniProt: APAF1: O14727
Identifier: R-HSA-6801271
Species: Homo sapiens
Compartment: secretory granule lumen
Primary external reference: UniProt: APAF1: O14727

DNA Sequence (1 results from a total of 1)

Identifier: R-HSA-6791347
Species: Homo sapiens
Compartment: nucleoplasm
Primary external reference: ENSEMBL: ENSEMBL:ENSG00000120868

Reaction (5 results from a total of 19)

Identifier: R-HSA-114254
Species: Homo sapiens
Compartment: cytosol
The apoptotic protease‑activating factor 1 (APAF1) is a cytosolic multidomain adapter protein containing an N‑terminal caspase recruitment domain (CARD), followed by a central nucleotide‑binding & oligomerization domain (NOD, also known as NB‑ARC) and a C‑terminal regulatory region with WD40 repeats which form the 7- and 8-bladed β-propellers (Inohara N and Nunez G 2003; Danot O et al. 2009; Yuan S et al. 2011). Under steady‑state, non‑apoptotic conditions, APAF1 exists as an ADP‑bound, autoinhibited monomer (Riedl SJ et al. 2005; Reubold TF et al. 2009). During apoptosis, cytochrome c (CYCS) is released from the mitochondrial intermembrane space to the cytosol where it binds APAF1 between the two WD40 repeat domains in the C‑terminal regulatory region (Zou et al. 1997; Liu X et al. 1996; Shalaeva DN et al. 2015; Zhou M et al. 2015). CYCS binding causes an upward rotation of the β-propeller region which is accompanied by conformational changes in APAF1 and the replacement of ADP by dATP or ATP triggering APAF1 oligomerization into a heptameric, wheel‑shaped signaling platform (Acehan D et al. 2002; Yu X et al. 2005, Kim HE et al. 2005; Yuan S et al. 2010, 2013; Li P et al. 1997; Jiang X & Wang X 2000; Zhou M et al. 2015). Moreover, the N-terminal CARD in the inactive APAF1 monomer is not shielded from other proteins by β–propellers. Hence, the APAF1 CARD may be free to interact with a procaspase-9 CARD either before or during apoptosome assembly (Yuan S et al. 2013). Physiological concentrations of calcium ion negatively affect the assembly of apoptosome and activation of CASP9 by inhibiting nucleotide exchange in the monomeric, autoinhibited APAF1 (Bao Q et al. 2007).
Identifier: R-HSA-6805507
Species: Homo sapiens
Compartment: cytosol
The binding of AVEN to apoptotic protease activating factor 1 (APAF1) is thought to interfere with the ability of APAF1 to self-associate during apoptosome assembly (Chau BN et al. 2000). The anti-apoptotic function of AVEN may require the proteolytic removal of the inhibitory N-terminus of AVEN (Melzer IM et al. 2012).
Identifier: R-HSA-6791348
Species: Homo sapiens
Compartment: cytosol, nucleoplasm
Once bound to the p53 response element in the promoter of the APAF1 gene, TP53 (p53) stimulates APAF1 transcription (Robles et al. 2001). APAF1 participates in the intrinsic apoptosis pathway, where its interaction with cytochrome C mediates the autocatalytic activation of pro-caspase-9 (Hu et al. 1999).
Identifier: R-HSA-6791349
Species: Homo sapiens
Compartment: nucleoplasm
TP53 (p53) binds the p53 response element in the promoter of the APAF1 gene (Robles et al. 2001).
Identifier: R-HSA-9007514
Species: Homo sapiens
Compartment: nucleoplasm
E2F1, presumably in complex with TFDP1 or TFDP2, binds the promoter of the APAF1 gene (Kikuchi et al. 2007).

Complex (5 results from a total of 12)

Identifier: R-HSA-114253
Species: Homo sapiens
Compartment: cytosol
Identifier: R-HSA-6804555
Species: Homo sapiens
Compartment: cytosol
Identifier: R-HSA-6804605
Species: Homo sapiens
Compartment: cytosol
Identifier: R-HSA-6804569
Species: Homo sapiens
Compartment: cytosol
Identifier: R-HSA-9627055
Species: Homo sapiens
Compartment: cytosol

Pathway (5 results from a total of 5)

Identifier: R-HSA-111458
Species: Homo sapiens
Compartment: cytosol
The apoptosome is a cytoplasmic protein complex of two major components ‑ the adapter protein apoptotic protease activating factor 1 (APAF1) and the protease caspase‑9 (CASP9) which interact with each other through their caspase recruitment domains (CARD) (Qin et al. 1999; Yuan S et al. 2010; Yuan S & Akey CW 2013). The function of the apoptosome is to assemble a multimeric complex between APAF1 and procaspase-9 CARDs to facilitate CASP9 activation (Jiang X and Wang X 2000; Srinivasrula SM et al. 2001; Shiozaki EN et al. 2002). The apoptosome is assembled upon APAF1 interaction with cytochrome c (CYCS), which is released from the mitochondrial intermembrane space during apoptosis (Zou H et al. 1997; Yuan S et al. 2013; Shakeri R et al. 2017). CYCS‑bound APAF1 undergoes ATP-mediated conformational changes and in the presence of CARD of CASP9 oligomerizes into a heptameric complex, which activates procaspase 9 (Zou H et al. 1997; Bratton SB et al. 2010; Acehan D et al. 2002; Yu X et al. 2005; Yuan S et al. 2010; Su TW et al. 2017). In the apoptosome, recruitment of caspase-9 may occur before oligomerization in the CARD disk, which presumably brings the caspase domain into proximity for their dimerization and activation (Su TW et al. 2017; Hu Q et al. 2014; Cheng TC et al. 2016). Once activated, CASP9 activates downstream effector caspases‑3 and ‑7. The activated effector caspases then cleave various cellular proteins.

Different models have been proposed to explain CASP9 activation: the “proximity‑driven dimerization model” and the “induced conformation model”. The first models states that upon binding to heptameric APAF1, monomers of procaspase‑9 are brought into close proximity at a high concentration (Acehan et al. 2002; Renatus et al. 2001). This induces dimerization which is sufficient for CASP9 activation whereas autoprocessing within the apoptosome complex merely stabilizes CASP9 dimer (Boatright KM et al. 2003; Pop C et al. 2006). The “induced conformation model” is based on the observation that CASP9 has a much higher level of catalytic activity when it's bound to the apoptosome. The model suggests that a conformational change occurs at the active site of CASP9 upon binding to APAF1 thus inducing CASP9 homodimerization and stabilizing it in the catalytically active conformation (Shiozaki EN et al. 2002). CASP9 activation may also involve formation of a multimeric CARD:CARD assembly between APAF1 and procaspase‑9 (Hu Q et al. 2014).

Identifier: R-HSA-111461
Species: Homo sapiens
Compartment: cytosol
Upon its release from the mitochondrial intermembrane space, cytochrome c (CYSC) binds to and causes an ATP-mediated conformational change in the cytoplasmic adaptor protein apoptotic protease‑activating factor 1 (APAF1). This conformational change triggers the formation of procaspase-9-activating oligomeric protein complex named apoptosome. The active caspase‑9 holoenzyme activates downstream effector caspases‑3 and ‑7. The activated effector caspases then cleave various cellular proteins.
Identifier: R-HSA-6803207
Species: Homo sapiens
TP53 (p53) transcriptionally regulates cytosolic caspase activators, such as APAF1, PIDD1, and NLRC4, and caspases themselves, such as CASP1, CASP6 and CASP10. These caspases and their activators are involved either in the intrinsic apoptosis pathway or in the extrinsic apoptosis pathway triggerred by death receptors or the inflammation-related cell death pyroptosis (Lin et al. 2000, Robles et al. 2001, Gupta et al. 2001, MacLachlan and El-Deiry 2002, Rikhof et al. 2003, Sadasivam et al. 2005, Brough and Rothwell 2007).
Identifier: R-HSA-418889
Species: Homo sapiens
In the presence of Netrin1, DCC and UNC5 generate attractive and repulsive signals to growing axons. In the absence of Netrin-1, DCC induces cell death signaling initiated via caspase cleavage of DCC and the interaction of caspase-9. Recent reports have shown that UNC5 receptors similarly induce apoptosis in the absence of Netrin-1. These reactions proceed without a requirement for cytochrome c release from mitochondria or interaction with apoptotic protease activating factor 1 (APAF1). DCC thus regulates an apoptosome-independent pathway for caspase activation. DCC and UNC-5 are hence defined as dependence receptors. Dependence receptors exhibit dual functions depending on the availability of ligand. They create cellular states of dependence on their respective ligands by either inducing apoptosis when unoccupied by the ligand, or inhibiting apoptosis in the presence of the ligand.
Identifier: R-HSA-5633008
Species: Homo sapiens
The tumor suppressor TP53 (p53) exerts its tumor suppressive role in part by regulating transcription of a number of genes involved in cell death, mainly apoptotic cell death. The majority of apoptotic genes that are transcriptional targets of TP53 promote apoptosis, but there are also several TP53 target genes that inhibit apoptosis, providing cells with an opportunity to attempt to repair the damage and/or recover from stress.
Pro-apoptotic transcriptional targets of TP53 involve TRAIL death receptors TNFRSF10A (DR4), TNFRSF10B (DR5), TNFRSF10C (DcR1) and TNFRSF10D (DcR2), as well as the FASL/CD95L death receptor FAS (CD95). TRAIL receptors and FAS induce pro-apoptotic signaling in response to external stimuli via extrinsic apoptosis pathway (Wu et al. 1997, Takimoto et al. 2000, Guan et al. 2001, Liu et al. 2004, Ruiz de Almodovar et al. 2004, Liu et al. 2005, Schilling et al. 2009, Wilson et al. 2013). IGFBP3 is a transcriptional target of TP53 that may serve as a ligand for a novel death receptor TMEM219 (Buckbinder et al. 1995, Ingermann et al. 2010).

TP53 regulates expression of a number of genes involved in the intrinsic apoptosis pathway, triggered by the cellular stress. Some of TP53 targets, such as BAX, BID, PMAIP1 (NOXA), BBC3 (PUMA) and probably BNIP3L, AIFM2, STEAP3, TRIAP1 and TP53AIP1, regulate the permeability of the mitochondrial membrane and/or cytochrome C release (Miyashita and Reed 1995, Oda et al. 2000, Samuels-Lev et al. 2001, Nakano and Vousden 2001, Sax et al. 2002, Passer et al. 2003, Bergamaschi et al. 2004, Li et al. 2004, Fei et al. 2004, Wu et al. 2004, Park and Nakamura 2005, Patel et al. 2008, Wang et al. 2012, Wilson et al. 2013). Other pro-apoptotic genes, either involved in the intrinsic apoptosis pathway, extrinsic apoptosis pathway or pyroptosis (inflammation-related cell death), which are transcriptionally regulated by TP53 are cytosolic caspase activators, such as APAF1, PIDD1, and NLRC4, and caspases themselves, such as CASP1, CASP6 and CASP10 (Lin et al. 2000, Robles et al. 2001, Gupta et al. 2001, MacLachlan and El-Deiry 2002, Rikhof et al. 2003, Sadasivam et al. 2005, Brough and Rothwell 2007).

It is uncertain how exactly some of the pro-apoptotic TP53 targets, such as TP53I3 (PIG3), RABGGTA, BCL2L14, BCL6, NDRG1 and PERP contribute to apoptosis (Attardi et al. 2000, Guo et al. 2001, Samuels-Lev et al. 2001, Contente et al. 2002, Ihrie et al. 2003, Bergamaschi et al. 2004, Stein et al. 2004, Phan and Dalla-Favera 2004, Jen and Cheung 2005, Margalit et al. 2006, Zhang et al. 2007, Saito et al. 2009, Davies et al. 2009, Giam et al. 2012).

TP53 is stabilized in response to cellular stress by phosphorylation on at least serine residues S15 and S20. Since TP53 stabilization precedes the activation of cell death genes, the TP53 tetramer phosphorylated at S15 and S20 is shown as a regulator of pro-apoptotic/pro-cell death genes. Some pro-apoptotic TP53 target genes, such as TP53AIP1, require additional phosphorylation of TP53 at serine residue S46 (Oda et al. 2000, Taira et al. 2007). Phosphorylation of TP53 at S46 is regulated by another TP53 pro-apoptotic target, TP53INP1 (Okamura et al. 2001, Tomasini et al. 2003). Additional post-translational modifications of TP53 may be involved in transcriptional regulation of genes presented in this pathway and this information will be included as evidence becomes available.

Activation of some pro-apoptotic TP53 targets, such as BAX, FAS, BBC3 (PUMA) and TP53I3 (PIG3) requires the presence of the complex of TP53 and an ASPP protein, either PPP1R13B (ASPP1) or TP53BP2 (ASPP2) (Samuels-Lev et al. 2001, Bergamaschi et al. 2004, Patel et al. 2008, Wilson et al. 2013), indicating how the interaction with specific co-factors modulates the cellular response/outcome.

TP53 family members TP63 and or TP73 can also activate some of the pro-apoptotic TP53 targets, such as FAS, BAX, BBC3 (PUMA), TP53I3 (PIG3), CASP1 and PERP (Bergamaschi et al. 2004, Jain et al. 2005, Ihrie et al. 2005, Patel et al. 2008, Schilling et al. 2009, Celardo et al. 2013).


For a review of the role of TP53 in apoptosis and pro-apoptotic transcriptional targets of TP53, please refer to Riley et al. 2008, Murray-Zmijewski et al. 2008, Bieging et al. 2014, Kruiswijk et al. 2015.

Icon (1 results from a total of 1)

Species: Homo sapiens
Curator: Steve Jupe
Designer: Cristoffer Sevilla
APAF1 icon
Apoptotic protease-activating factor 1
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