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Gene Review

PYCARD  -  PYD and CARD domain containing

Homo sapiens

Synonyms: ASC, Apoptosis-associated speck-like protein containing a CARD, CARD5, Caspase recruitment domain-containing protein 5, PYD and CARD domain-containing protein, ...
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Disease relevance of PYCARD


Psychiatry related information on PYCARD

  • Despite the large overlap of these two scales, they measure somewhat different aspects of "Panic-Fear". The ASC measures a situational response (state variable) to breathing difficulties, while the MMPI measures a more stable, diffuse, and global personality characteristic (trait variable) [5].
  • Parents help ease separation anxiety in ASC (ambulatory surgery center) [6].

High impact information on PYCARD

  • Here we show that wild-type Francisella, which reach the cytosol, but not Francisella mutants that remain localized to the vacuole, induced a host defense response in macrophages, which is dependent on caspase-1 and the death-fold containing adaptor protein ASC [7].
  • Innate immunity against Francisella tularensis is dependent on the ASC/caspase-1 axis [7].
  • The PAAD/PYRIN-family protein ASC is a dual regulator of a conserved step in nuclear factor kappaB activation pathways [8].
  • Blocking of endogenous ASC expression by small-interfering RNA (siRNA) reduced the apoptotic response and inhibited translocation of Bax to mitochondria in response to p53 or genotoxic insult, suggesting that ASC is required to translocate Bax to the mitochondria [9].
  • When ectopically expressed, ASC interacted directly with Bax, colocalized with Bax to the mitochondria, induced cytochrome c release with a significant reduction of mitochondrial membrane potential and resulted in the activation of caspase-9, -2 and -3 [9].

Chemical compound and disease context of PYCARD


Biological context of PYCARD

  • Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC)/target of methylation-induced silencing/PYCARD represents one of only two proteins encoded in the human genome that contains a caspase recruitment domain (CARD) together with a pyrin, AIM, ASC, and death domain-like (PAAD)/PYRIN/DAPIN domain [13].
  • Interaction between pyrin and the apoptotic speck protein (ASC) modulates ASC-induced apoptosis [14].
  • These results are the first to indicate that caspase-8 plays an important role in the ASC-mediated NF-kappaB activation, and that the ASC-mediated NF-kappaB activation actually induces physiologically relevant gene expression [15].
  • Exon 1 of pyrin and exon 1 of ASC show 42% sequence similarity and resemble death domain-related structures in modeling studies [14].
  • In the present paper, we describe characterization of human PAAD-only protein-1 (POP1)/ASC2, which is highly homologous with the PAAD domain of ASC, and which probably originated by gene duplication on chromosome 16 [16].

Anatomical context of PYCARD

  • Using pyrin as a "bait" to probe a yeast two-hybrid library made from neutrophil cDNA, we isolated apoptotic speck protein containing a caspase recruitment domain (CARD) (ASC), a proapoptotic protein that induces the formation of large cytosolic "specks" in transfected cells [14].
  • We found that when HeLa cells are transfected with ASC, specks are formed [14].
  • We show here that ASC binds by its CARD to procaspase-1 and to adapter proteins involved in caspase-1 activation, thereby regulating cytokine pro-IL-1beta activation by this protease in THP-1 monocytes [13].
  • ASC mRNA levels were comparable in RA and OA tissue, FLS, and macrophages, and were depressed by TNFalpha in macrophages [17].
  • Caspase-8 deficiency rescued mouse fibroblasts from apoptosis induced by ASC oligomerization [18].

Associations of PYCARD with chemical compounds

  • The role of vitamin C (ascorbic acid, ASC), a known modulator of the cellular redox status, in regulating mitotic entry was investigated in this study [19].
  • RNA expression was restored by treatment with the demethylating agent 5-aza-2'-deoxycytidine, in 4 of 4 methylated cell lines that lacked the TMS1 transcript [20].
  • Intron 9 carries a retrotransposon-like element, Tms1, which might be responsible for downstream deletion events in which a heptanucleotide, ATTAGCT, might have been involved [21].
  • In the colon, ASC was detected in mature epithelial cells facing the luminal side rather than immature cells located deeper in the crypts [22].
  • Methylation of the TMS1 gene was detected using methylation-specific PCR followed by bisulfite-modification of DNA [23].
  • Induction of TMS1/ASC by TNFalpha was blocked by co-expression of a dominant negative IkappaBalpha, small interfering RNA-mediated knockdown of RelA/p65, or concurrent treatment with SP600125, indicating a requirement for the nuclear factor-kappaB (NF-kappaB) and jun kinase signaling pathways [24].

Physical interactions of PYCARD

  • In the absence of stimuli, wild-type cryopyrin was unable to bind to ASC, whereas the three mutants coimmunoprecipitated with ASC, suggesting a mechanism involved in the constitutive activation of mutant proteins [25].
  • The CARD domain of CARD12 interacts selectively with the CARD domain of ASC, a recently identified proapoptotic protein [26].
  • Phosphorylation mutants of p53 show differential complex formation with putative dehydrogenase Tms1 of fission yeast [27].

Co-localisations of PYCARD


Regulatory relationships of PYCARD

  • In addition, PYPAF1 induces caspase-1-dependent cytokine processing when co-expressed with ASC [28].
  • In gene transfer experiments PAN1 enhances caspase-1 activation and IL-1beta secretion in collaboration with ASC [29].
  • ASC directs NF-kappaB activation by regulating receptor interacting protein-2 (RIP2) caspase-1 interactions [30].

Other interactions of PYCARD

  • We also show here that PAN1 binds via its PYRIN domain to ASC, an adapter protein involved in caspase-1 activation [29].
  • This signaling was mimicked by oligomerization of ASC, suggesting that cryopyrin activates downstream targets as reported for other Nod family members [31].
  • However, expression of ASC uniformly interferes with caspase-1 activation and IL-1beta secretion induced by proinflammatory stimuli such as LPS and TNF, suggesting pathway competition [13].
  • We demonstrate that POP1/ASC2 associates with ASC via PAAD-PAAD interactions and modulates NF-kappa B and pro-caspase-1 regulation by this adapter protein [16].
  • Moreover, ASC also recruits procaspase-1 into ASC-formed cytosolic specks, separating it from Cardiak [13].

Analytical, diagnostic and therapeutic context of PYCARD


  1. Methylation of the ASC gene promoter is associated with aggressive prostate cancer. Collard, R.L., Harya, N.S., Monzon, F.A., Maier, C.E., O'Keefe, D.S. Prostate (2006) [Pubmed]
  2. TMS1, a novel proapoptotic caspase recruitment domain protein, is a target of methylation-induced gene silencing in human breast cancers. Conway, K.E., McConnell, B.B., Bowring, C.E., Donald, C.D., Warren, S.T., Vertino, P.M. Cancer Res. (2000) [Pubmed]
  3. Methylation-induced silencing of ASC and the effect of expressed ASC on p53-mediated chemosensitivity in colorectal cancer. Ohtsuka, T., Liu, X.F., Koga, Y., Kitajima, Y., Nakafusa, Y., Ha, C.W., Lee, S.W., Miyazaki, K. Oncogene (2006) [Pubmed]
  4. Epigenetic inactivation of TMS1/ASC in ovarian cancer. Terasawa, K., Sagae, S., Toyota, M., Tsukada, K., Ogi, K., Satoh, A., Mita, H., Imai, K., Tokino, T., Kudo, R. Clin. Cancer Res. (2004) [Pubmed]
  5. Panic-fear in asthma: generalized personality trait vs. specific situational state. Dirks, J.F., Fross, K.H., Evans, N.W. The Journal of asthma research. (1977) [Pubmed]
  6. Parents help ease separation anxiety in ASC (ambulatory surgery center). Patterson, P. OR manager. (1990) [Pubmed]
  7. Innate immunity against Francisella tularensis is dependent on the ASC/caspase-1 axis. Mariathasan, S., Weiss, D.S., Dixit, V.M., Monack, D.M. J. Exp. Med. (2005) [Pubmed]
  8. The PAAD/PYRIN-family protein ASC is a dual regulator of a conserved step in nuclear factor kappaB activation pathways. Stehlik, C., Fiorentino, L., Dorfleutner, A., Bruey, J.M., Ariza, E.M., Sagara, J., Reed, J.C. J. Exp. Med. (2002) [Pubmed]
  9. ASC is a Bax adaptor and regulates the p53-Bax mitochondrial apoptosis pathway. Ohtsuka, T., Ryu, H., Minamishima, Y.A., Macip, S., Sagara, J., Nakayama, K.I., Aaronson, S.A., Lee, S.W. Nat. Cell Biol. (2004) [Pubmed]
  10. ASC/TMS1, a caspase-1 activating adaptor, is downregulated by aberrant methylation in human melanoma. Guan, X., Sagara, J., Yokoyama, T., Koganehira, Y., Oguchi, M., Saida, T., Taniguchi, S. Int. J. Cancer (2003) [Pubmed]
  11. Comment on Rice ASC, Maton S, the Postherpetic Neuralgia Study Group (UK), gabapentin in postherpetic neuralgia: a randomized, double blind, placebo-controlled study. Bowsher, D. Pain (2002) [Pubmed]
  12. Phorbol esters rapidly attenuate glutamine uptake and growth in human colon carcinoma cells. Pawlik, T.M., Souba, W.W., Sweeney, T.J., Bode, B.P. J. Surg. Res. (2000) [Pubmed]
  13. Apoptosis-associated speck-like protein containing a caspase recruitment domain is a regulator of procaspase-1 activation. Stehlik, C., Lee, S.H., Dorfleutner, A., Stassinopoulos, A., Sagara, J., Reed, J.C. J. Immunol. (2003) [Pubmed]
  14. Interaction between pyrin and the apoptotic speck protein (ASC) modulates ASC-induced apoptosis. Richards, N., Schaner, P., Diaz, A., Stuckey, J., Shelden, E., Wadhwa, A., Gumucio, D.L. J. Biol. Chem. (2001) [Pubmed]
  15. ASC-mediated NF-kappaB activation leading to interleukin-8 production requires caspase-8 and is inhibited by CLARP. Hasegawa, M., Imamura, R., Kinoshita, T., Matsumoto, N., Masumoto, J., Inohara, N., Suda, T. J. Biol. Chem. (2005) [Pubmed]
  16. The PAAD/PYRIN-only protein POP1/ASC2 is a modulator of ASC-mediated nuclear-factor-kappa B and pro-caspase-1 regulation. Stehlik, C., Krajewska, M., Welsh, K., Krajewski, S., Godzik, A., Reed, J.C. Biochem. J. (2003) [Pubmed]
  17. Expression and regulation of cryopyrin and related proteins in rheumatoid arthritis synovium. Rosengren, S., Hoffman, H.M., Bugbee, W., Boyle, D.L. Ann. Rheum. Dis. (2005) [Pubmed]
  18. ASC is an activating adaptor for NF-kappa B and caspase-8-dependent apoptosis. Masumoto, J., Dowds, T.A., Schaner, P., Chen, F.F., Ogura, Y., Li, M., Zhu, L., Katsuyama, T., Sagara, J., Taniguchi, S., Gumucio, D.L., Núñez, G., Inohara, N. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  19. Vitamin C transiently arrests cancer cell cycle progression in S phase and G2/M boundary by modulating the kinetics of activation and the subcellular localization of Cdc25C phosphatase. Thomas, C.G., Vezyraki, P.E., Kalfakakou, V.P., Evangelou, A.M. J. Cell. Physiol. (2005) [Pubmed]
  20. Aberrant methylation of TMS1 in small cell, non small cell lung cancer and breast cancer. Virmani, A., Rathi, A., Sugio, K., Sathyanarayana, U.G., Toyooka, S., Kischel, F.C., Tonk, V., Padar, A., Takahashi, T., Roth, J.A., Euhus, D.M., Minna, J.D., Gazdar, A.F. Int. J. Cancer (2003) [Pubmed]
  21. The nucleotide sequence of a nodule-specific gene, Nms-25 of Medicago sativa: its primary evolution via exon-shuffling and retrotransposon-mediated DNA rearrangements. Végh, Z., Vincze, E., Kadirov, R., Tóth, G., Kiss, G.B. Plant Mol. Biol. (1990) [Pubmed]
  22. Expression of apoptosis-associated speck-like protein containing a caspase recruitment domain, a pyrin N-terminal homology domain-containing protein, in normal human tissues. Masumoto, J., Taniguchi, S., Nakayama, J., Shiohara, M., Hidaka, E., Katsuyama, T., Murase, S., Sagara, J. J. Histochem. Cytochem. (2001) [Pubmed]
  23. A proapoptotic caspase recruitment domain protein gene, TMS1, is hypermethylated in human breast and gastric cancers. Moriai, R., Tsuji, N., Kobayashi, D., Yagihashi, A., Namiki, Y., Takahashi, H., Watanabe, N. Anticancer Res. (2002) [Pubmed]
  24. Dual role of TMS1/ASC in death receptor signaling. Parsons, M.J., Vertino, P.M. Oncogene (2006) [Pubmed]
  25. Cryopyrin-induced interleukin 1beta secretion in monocytic cells: enhanced activity of disease-associated mutants and requirement for ASC. Dowds, T.A., Masumoto, J., Zhu, L., Inohara, N., Núñez, G. J. Biol. Chem. (2004) [Pubmed]
  26. Human CARD12 is a novel CED4/Apaf-1 family member that induces apoptosis. Geddes, B.J., Wang, L., Huang, W.J., Lavellee, M., Manji, G.A., Brown, M., Jurman, M., Cao, J., Morgenstern, J., Merriam, S., Glucksmann, M.A., DiStefano, P.S., Bertin, J. Biochem. Biophys. Res. Commun. (2001) [Pubmed]
  27. Phosphorylation mutants of p53 show differential complex formation with putative dehydrogenase Tms1 of fission yeast. Wagner, P. Eur. J. Biochem. (1997) [Pubmed]
  28. PYPAF7, a novel PYRIN-containing Apaf1-like protein that regulates activation of NF-kappa B and caspase-1-dependent cytokine processing. Wang, L., Manji, G.A., Grenier, J.M., Al-Garawi, A., Merriam, S., Lora, J.M., Geddes, B.J., Briskin, M., DiStefano, P.S., Bertin, J. J. Biol. Chem. (2002) [Pubmed]
  29. PAN1/NALP2/PYPAF2, an inducible inflammatory mediator that regulates NF-kappaB and caspase-1 activation in macrophages. Bruey, J.M., Bruey-Sedano, N., Newman, R., Chandler, S., Stehlik, C., Reed, J.C. J. Biol. Chem. (2004) [Pubmed]
  30. ASC directs NF-kappaB activation by regulating receptor interacting protein-2 (RIP2) caspase-1 interactions. Sarkar, A., Duncan, M., Hart, J., Hertlein, E., Guttridge, D.C., Wewers, M.D. J. Immunol. (2006) [Pubmed]
  31. Regulation of cryopyrin/Pypaf1 signaling by pyrin, the familial Mediterranean fever gene product. Dowds, T.A., Masumoto, J., Chen, F.F., Ogura, Y., Inohara, N., Núñez, G. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
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