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Gene Review

APAF1  -  apoptotic peptidase activating factor 1

Homo sapiens

Synonyms: APAF-1, Apoptotic protease-activating factor 1, CED4, KIAA0413
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Disease relevance of APAF1


Psychiatry related information on APAF1


High impact information on APAF1

  • Cytochrome c (CC)-initiated Apaf-1 apoptosome formation represents a key initiating event in apoptosis [6].
  • Here we show that physiological levels of nucleotides inhibit the CC-initiated apoptosome formation and caspase-9 activation by directly binding to CC on several key lysine residues and thus preventing CC interaction with Apaf-1 [6].
  • We report here the identification of a novel protein, Smac, which promotes caspase activation in the cytochrome c/Apaf-1/caspase-9 pathway [7].
  • We report here the purification and cDNA cloning of Apaf-1, a novel 130 kd protein from HeLa cell cytosol that participates in the cytochrome c-dependent activation of caspase-3 [8].
  • The NH2-terminal 85 amino acids of Apaf-1 show 21% identity and 53% similarity to the NH2-terminal prodomain of the Caenorhabditis elegans caspase, CED-3 [8].

Chemical compound and disease context of APAF1


Biological context of APAF1

  • Finally, several genes in this pathway, including APAF1, CASP9 and CASP3, have been shown to be associated with dramatic defects in neuronal cell number and brain size when mutated in mice [14].
  • The induction of APAF1 and two genes coding for two subunits of cytochrome c supports a previous report showing increased apoptosis in lymphocytes from SLE patients [15].
  • Thus, neutrophils have a lowered threshold requirement for cytochrome c in the Apaf-1-dependent cell death pathway [16].
  • Finally, we isolated the promoter region of the Apaf-1 gene and found a putative binding site for E2F [17].
  • However, when dATP is added to the cytochrome c-bound Apaf-1 complex, complete oligomerization occurs, suggesting that oligomerization is driven by hydrolysis of dATP [18].

Anatomical context of APAF1


Associations of APAF1 with chemical compounds

  • This was supported by the observation that ATP, but not the nonhydrolyzable adenosine 5'-O-(thiotriphosphate), can induce oligomerization of the Apaf-1-cytochrome c complex [18].
  • Subsequently, the Apaf-1/caspase-9 holoenzyme complex recruits the effector caspase-3 via an interaction between the active site cysteine in caspase-9 and the critical aspartate, which is the cleavage site for generating the large and small subunits of caspase-3 that constitute the activated form of caspase-3 [20].
  • These results suggest that in a certain type of HNSCCs, the inhibition of Casp9 activity and Apaf-1 expression may represent a mechanism of acquired cisplatin resistance [9].
  • Our data suggest that Ca(2+) inhibits caspase activation during Ca(2+)-mediated neuron death by triggering the degradation of the cytochrome c-binding protein APAF-1 [10].
  • Treatment of these cells with 5-aza-2'-deoxycytidine, a specific inhibitor of DNA methylation, restored the expression of Apaf-1 [21].

Physical interactions of APAF1


Enzymatic interactions of APAF1


Regulatory relationships of APAF1


Other interactions of APAF1


Analytical, diagnostic and therapeutic context of APAF1


  1. Plasma membrane sequestration of apoptotic protease-activating factor-1 in human B-lymphoma cells: a novel mechanism of chemoresistance. Sun, Y., Orrenius, S., Pervaiz, S., Fadeel, B. Blood (2005) [Pubmed]
  2. Caspase-9 and Apaf-1 are expressed and functionally active in human neuroblastoma tumor cell lines with 1p36 LOH and amplified MYCN. Teitz, T., Wei, T., Liu, D., Valentine, V., Valentine, M., Grenet, J., Lahti, J.M., Kidd, V.J. Oncogene (2002) [Pubmed]
  3. D,L-Sulforaphane-induced cell death in human prostate cancer cells is regulated by inhibitor of apoptosis family proteins and Apaf-1. Choi, S., Lew, K.L., Xiao, H., Herman-Antosiewicz, A., Xiao, D., Brown, C.K., Singh, S.V. Carcinogenesis (2007) [Pubmed]
  4. Decreased expression of Apaf-1 with progression of melanoma. Mustika, R., Budiyanto, A., Nishigori, C., Ichihashi, M., Ueda, M. Pigment Cell Res. (2005) [Pubmed]
  5. Apoptosome inactivation rescues proneural and neural cells from neurodegeneration. Cozzolino, M., Ferraro, E., Ferri, A., Rigamonti, D., Quondamatteo, F., Ding, H., Xu, Z.S., Ferrari, F., Angelini, D.F., Rotilio, G., Cattaneo, E., Carrì, M.T., Cecconi, F. Cell Death Differ. (2004) [Pubmed]
  6. Intracellular nucleotides act as critical prosurvival factors by binding to cytochrome C and inhibiting apoptosome. Chandra, D., Bratton, S.B., Person, M.D., Tian, Y., Martin, A.G., Ayres, M., Fearnhead, H.O., Gandhi, V., Tang, D.G. Cell (2006) [Pubmed]
  7. Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Du, C., Fang, M., Li, Y., Li, L., Wang, X. Cell (2000) [Pubmed]
  8. Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3. Zou, H., Henzel, W.J., Liu, X., Lutschg, A., Wang, X. Cell (1997) [Pubmed]
  9. Inhibition of caspase-9 activity and Apaf-1 expression in cisplatin-resistant head and neck squamous cell carcinoma cells. Kuwahara, D., Tsutsumi, K., Oyake, D., Ohta, T., Nishikawa, H., Koizuka, I. Auris, nasus, larynx. (2003) [Pubmed]
  10. Ca(2+)-induced inhibition of apoptosis in human SH-SY5Y neuroblastoma cells: degradation of apoptotic protease activating factor-1 (APAF-1). Reimertz, C., Kögel, D., Lankiewicz, S., Poppe, M., Prehn, J.H. J. Neurochem. (2001) [Pubmed]
  11. Inactivation of the apoptosis effector Apaf-1 in malignant melanoma. Soengas, M.S., Capodieci, P., Polsky, D., Mora, J., Esteller, M., Opitz-Araya, X., McCombie, R., Herman, J.G., Gerald, W.L., Lazebnik, Y.A., Cordón-Cardó, C., Lowe, S.W. Nature (2001) [Pubmed]
  12. Apaf-1/cytochrome c-independent and Smac-dependent induction of apoptosis in multiple myeloma (MM) cells. Chauhan, D., Hideshima, T., Rosen, S., Reed, J.C., Kharbanda, S., Anderson, K.C. J. Biol. Chem. (2001) [Pubmed]
  13. Role of reactive oxygen species and spinal cord apoptotic genes in the development of neuropathic pain. Siniscalco, D., Fuccio, C., Giordano, C., Ferraraccio, F., Palazzo, E., Luongo, L., Rossi, F., Roth, K.A., Maione, S., de Novellis, V. Pharmacol. Res. (2007) [Pubmed]
  14. A primate-specific acceleration in the evolution of the caspase-dependent apoptosis pathway. Vallender, E.J., Lahn, B.T. Hum. Mol. Genet. (2006) [Pubmed]
  15. Gene expression profiles in human cells submitted to genotoxic stress. Sakamoto-Hojo, E.T., Mello, S.S., Pereira, E., Fachin, A.L., Cardoso, R.S., Junta, C.M., Sandrin-Garcia, P., Donadi, E.A., Passos, G.A. Mutat. Res. (2003) [Pubmed]
  16. The apoptosome pathway to caspase activation in primary human neutrophils exhibits dramatically reduced requirements for cytochrome C. Murphy, B.M., O'Neill, A.J., Adrain, C., Watson, R.W., Martin, S.J. J. Exp. Med. (2003) [Pubmed]
  17. Apaf-1 is a mediator of E2F-1-induced apoptosis. Furukawa, Y., Nishimura, N., Furukawa, Y., Satoh, M., Endo, H., Iwase, S., Yamada, H., Matsuda, M., Kano, Y., Nakamura, M. J. Biol. Chem. (2002) [Pubmed]
  18. Cytochrome c and dATP-mediated oligomerization of Apaf-1 is a prerequisite for procaspase-9 activation. Saleh, A., Srinivasula, S.M., Acharya, S., Fishel, R., Alnemri, E.S. J. Biol. Chem. (1999) [Pubmed]
  19. Requirement of cytochrome c for apoptosis in human cells. Matapurkar, A., Lazebnik, Y. Cell Death Differ. (2006) [Pubmed]
  20. Chemical-induced apoptosis: formation of the Apaf-1 apoptosome. Cain, K. Drug Metab. Rev. (2003) [Pubmed]
  21. Methylation silencing of the Apaf-1 gene in acute leukemia. Furukawa, Y., Sutheesophon, K., Wada, T., Nishimura, M., Saito, Y., Ishii, H., Furukawa, Y. Mol. Cancer Res. (2005) [Pubmed]
  22. Heat-shock protein 70 inhibits apoptosis by preventing recruitment of procaspase-9 to the Apaf-1 apoptosome. Beere, H.M., Wolf, B.B., Cain, K., Mosser, D.D., Mahboubi, A., Kuwana, T., Tailor, P., Morimoto, R.I., Cohen, G.M., Green, D.R. Nat. Cell Biol. (2000) [Pubmed]
  23. The Apaf-1 internal ribosome entry segment attains the correct structural conformation for function via interactions with PTB and unr. Mitchell, S.A., Spriggs, K.A., Coldwell, M.J., Jackson, R.J., Willis, A.E. Mol. Cell (2003) [Pubmed]
  24. VEGF(165) promotes survival of leukemic cells by Hsp90-mediated induction of Bcl-2 expression and apoptosis inhibition. Dias, S., Shmelkov, S.V., Lam, G., Rafii, S. Blood (2002) [Pubmed]
  25. The machinery of programmed cell death. Zimmermann, K.C., Bonzon, C., Green, D.R. Pharmacol. Ther. (2001) [Pubmed]
  26. APAF-1 signaling in human melanoma. Anichini, A., Mortarini, R., Sensi, M., Zanon, M. Cancer Lett. (2006) [Pubmed]
  27. Regulation of apoptotic protease activating factor-1 oligomerization and apoptosis by the WD-40 repeat region. Adrain, C., Slee, E.A., Harte, M.T., Martin, S.J. J. Biol. Chem. (1999) [Pubmed]
  28. Bcl-XL interacts with Apaf-1 and inhibits Apaf-1-dependent caspase-9 activation. Hu, Y., Benedict, M.A., Wu, D., Inohara, N., Núñez, G. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  29. Differential regulation and ATP requirement for caspase-8 and caspase-3 activation during CD95- and anticancer drug-induced apoptosis. Ferrari, D., Stepczynska, A., Los, M., Wesselborg, S., Schulze-Osthoff, K. J. Exp. Med. (1998) [Pubmed]
  30. Regularly methylated novel pro-apoptotic genes associated with recurrence in transitional cell carcinoma of the bladder. Christoph, F., Weikert, S., Kempkensteffen, C., Krause, H., Schostak, M., Miller, K., Schrader, M. Int. J. Cancer (2006) [Pubmed]
  31. A structure of the human apoptosome at 12.8 A resolution provides insights into this cell death platform. Yu, X., Acehan, D., Ménétret, J.F., Booth, C.R., Ludtke, S.J., Riedl, S.J., Shi, Y., Wang, X., Akey, C.W. Structure (Camb.) (2005) [Pubmed]
  32. Mutational analysis of Chk1, Chk2, Apaf1 and Rb1 in human malignant melanoma cell lines. Papp, T., Niemetz, A., Dosdahl, N., Kumar, K., Schiffmann, D. Oncol. Rep. (2007) [Pubmed]
  33. Apaf-1 is a transcriptional target for E2F and p53. Moroni, M.C., Hickman, E.S., Lazzerini Denchi, E., Caprara, G., Colli, E., Cecconi, F., Müller, H., Helin, K. Nat. Cell Biol. (2001) [Pubmed]
  34. Three new types of Apaf-1 in mammalian cells. Hahn, C., Hirsch, B., Jahnke, D., Dürkop, H., Stein, H. Biochem. Biophys. Res. Commun. (1999) [Pubmed]
  35. Apaf-1 expression in human cutaneous melanoma progression and in pigmented nevi. Niedojadło, K., Łabedzka, K., Łada, E., Milewska, A., Chwirot, B.W. Pigment Cell Res. (2006) [Pubmed]
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