, Volume 9, Issue 1, pp 5–18 | Cite as

TMS1/ASC: The cancer connection



TMS1/ASC is a bipartite protein comprising two protein-protein interaction domains, a pyrin domain (PYD) and a caspase recruitment domain (CARD). Proteins containing these domains play pivotal roles in regulating apoptosis and immune response pathways, and mutations in a number of PYD- and CARD-containing proteins have been linked to autoinflammatory diseases and cancer. Indeed, one of the ways in which TMS1/ASC was identified was as a target of methylation-mediated silencing in breast cancer cells. This review discusses the mounting evidence supporting a correlation between the silencing of TMS1/ASC expression and cancer. In addition, it addresses the reported functions of TMS1/ASC that include apoptosis, activation of inflammatory caspases and regulation of NF-kappa B, and discusses the potential ways in which loss of TMS1/ASC contributes to carcinogenesis.

ASC apoptosis cancer CARD caspase NF-κB pyrin domain TMS1 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Martinon F, Hofmann K, Tschopp J. The pyrin domain: A possible member of the death domain-fold family implicated in apoptosis and inflammation. Curr Biol 2001; 11: R118–R120.Google Scholar
  2. 2.
    Fairbrother WJ, Gordon NC, Humke EW, et al. The PYRIN domain: A member of the death domain-fold superfamily. Protein Sci 2001; 10: 1911–1918.Google Scholar
  3. 3.
    Staub E, Dahl E, Rosenthal A. The DAPIN family: A novel domain links apoptotic and interferon response proteins. Trends Biochem Sci 2001; 26: 83–85.Google Scholar
  4. 4.
    Pawlowski K, Pio F, Chu Z, Reed JC, Godzik A. PAAD-A new protein domain associated with apoptosis, cancer and autoimmune diseases. Trends Biochem Sci 2001; 26: 85–87.Google Scholar
  5. 5.
    Weber CH, Vincenz C. The death domain superfamily: A tale of two interfaces? Trends Biochem Sci 2001; 26: 475–481.Google Scholar
  6. 6.
    Martin SJ. Dealing the CARDs between life and death. Trends Cell Biol 2001; 11: 188–189.Google Scholar
  7. 7.
    Conway KE, McConnell BB, Bowring CE, Donald CD, Warren ST, Vertino PM. TMS1, a novel proapoptotic caspase recruitment domain protein, is a target of methylation-induced gene silencing in human breast cancers. Cancer Res 2000; 60: 6236–6242.Google Scholar
  8. 8.
    DeYoung KL, Ray ME, Su YA, et al. Cloning a novel member of the human interferon-inducible gene family associated with control of tumorigenicity in a model of human melanoma. Oncogene 1997; 15: 453–457.Google Scholar
  9. 9.
    Kastner DL, O'Shea JJ. A fever gene comes in from the cold. Nat Genet 2001; 29: 241–242.Google Scholar
  10. 10.
    Willis TG, Jadayel DM, Du MQ, et al. Bcl10 is involved in t(1;14)(p22;q32) of MALT B cell lymphoma and mutated in multiple tumor types. Cell 1999; 96: 35–45.Google Scholar
  11. 11.
    Zhang Q, Siebert R, Yan M, et al. Inactivating mutations and overexpression of BCL10, a caspase recruitment domain-containing gene, in MALT lymphoma with t(1;14)(p22;q32). Nat Genet 1999; 22: 63–68.Google Scholar
  12. 12.
    Masumoto J, Taniguchi S, Ayukawa K, et al. ASC, a novel 22-kDa protein, aggregates during apoptosis of human promyelocytic leukemia HL-60 cells. J Biol Chem 1999; 274: 33835–33838.Google Scholar
  13. 13.
    Martinon F, Burns K, Tschopp J. The inflammasome: A molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell 2002; 10: 417–426.Google Scholar
  14. 14.
    Manji GA, Wang L, Geddes BJ, et al. PYPAF1, a PYRIN-containing Apaf1-like protein that assembles with ASC and regulates activation of NF-kappa B. J Biol Chem 2002; 277: 11570–11575.Google Scholar
  15. 15.
    Srinivasula SM, Poyet JL, Razmara M, Datta P, Zhang Z, Alnemri ES. The PYRIN-CARD protein ASC is an activating adaptor for caspase-1. J Biol Chem 2002; 277: 21119–21122.Google Scholar
  16. 16.
    Moriai R, Tsuji N, Kobayashi D, et al. A proapoptotic caspase recruitment domain protein gene, TMS1, is hypermethylated in human breast and gastric cancers. Anticancer Res 2002; 22: 4163–4168.Google Scholar
  17. 17.
    Virmani A, Rathi A, Sugio K, et al. Aberrant methylation of TMS1in small cell, non small cell lung cancer and breast cancer. Int J Cancer 2003; 106: 198–204.Google Scholar
  18. 18.
    Guan X, Sagara J, Yokoyama T, et al. ASC/TMS1, a caspase-1 activating adaptor, is downregulated by aberrant metylation in human melanoma. Int J Cancer 2003; 107: 202–208.Google Scholar
  19. 19.
    Bird AP. CpG-rich islands and the function of DNA methylation. Nature 1986; 321: 209–213.Google Scholar
  20. 20.
    Antequera F, Bird A. CpG islands. Exs 1993; 64: 169–185.Google Scholar
  21. 21.
    Lander ES, Linton LM, Birren B, et al. Initial sequencing and analysis of the human genome. Nature 2001; 409: 860–921.Google Scholar
  22. 22.
    Keshet I, Yisraeli J, Cedar H. Effect of regional DNA methylation on gene expression. Proc Natl Acad Sci U S A 1985; 82: 2560–2564.Google Scholar
  23. 23.
    Cross SH, Bird AP. CpG islands and genes. Curr Opin Genet Dev 1995; 5: 309–314.Google Scholar
  24. 24.
    Wigler M, Levy D, Perucho M. The somatic replication of DNA methylation. Cell 1981; 24: 33–40.Google Scholar
  25. 25.
    Baylin SB, Herman JG, Graff JR, Vertino PM, Issa JP. Alterations in DNA methylation:Afundamental aspect of neoplasia. Adv Cancer Res 1998; 72: 141–196.Google Scholar
  26. 26.
    Jones PA, Laird PW. Cancer epigenetics comes of age. Nat Genet 1999; 21: 163–167.Google Scholar
  27. 27.
    Bachman KE, Herman JG, Corn PG, et al. Methylation-associated silencing of the tissue inhibitor of metalloproteinase-3 gene suggest a suppressor role in kidney, brain, and other human cancers. Cancer Res 1999; 59: 798–802.Google Scholar
  28. 28.
    Esteller M, Corn PG, Baylin SB, Herman JG. A gene hypermethylation profile of human cancer. Cancer Res 2001; 61: 3225–3229.Google Scholar
  29. 29.
    van't Veer LJ, Dai H, van de Vijver MJ, et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature 2002; 415: 530–536.Google Scholar
  30. 30.
    Schmitt AO, Specht T, Beckmann G, et al. Exhaustive mining of EST libraries for genes differentially expressed in normal and tumour tissues. Nucleic Acids Res 1999; 27: 4251–4260.Google Scholar
  31. 31.
    Levine JJ, Stimson-Crider KM, Vertino PM. Effects of methylation on expression of TMS1/ASC in human breast cancer cells. Oncogene 2003; 22: 3475–3488.Google Scholar
  32. 32.
    Masumoto J, Taniguchi S, Nakayama J, et al. Expression of apoptosis-associated speck-like protein containing a caspase recruitment domain, a pyrin N-terminal homology domain-containing protein, in normal human tissues. J Histochem Cytochem 2001; 49: 1269–1275.Google Scholar
  33. 33.
    Zhou P, Chou J, Olea RS, Yuan J, Wagner G. Solution structure of Apaf-1 CARD and its interaction with caspase-9 CARD: A structural basis for specific adaptor/caspase interaction. Proc Natl Acad Sci USA 1999; 96: 11265–11270.Google Scholar
  34. 34.
    Chou JJ, Matsuo H, Duan H, Wagner G. Solution structure of the RAIDD CARD and model for CARD/CARD interaction in caspase-2 and caspase-9 recruitment. Cell 1998; 94: 171–180.Google Scholar
  35. 35.
    Inohara N, Nunez G. NODs: Intracellular proteins involved in inflammation and apoptosis. Nat Rev Immunol 2003; 3: 371–382.Google Scholar
  36. 36.
    Deveraux QL, Reed JC. IAP family proteins-suppressors of apoptosis. Genes Dev 1999; 13: 239–252.Google Scholar
  37. 37.
    Inohara N, del Peso L, Koseki T, Chen S, Nunez G. RICK, a novel protein kinase containing a caspase recruitment domain, interacts with CLARP and regulates CD95-mediated apoptosis. J Biol Chem 1998; 273: 12296–12300.Google Scholar
  38. 38.
    Thome M, Hofmann K, Burns K, et al. Identification of CARDIAK, a RIP-like kinase that associates with caspase-1. Curr Biol 1998; 8: 885–888.Google Scholar
  39. 39.
    McCarthy JV, Ni J, Dixit VM. RIP2 is a novel NF-kappaB-activating and cell death-inducing kinase. J Biol Chem 1998; 273: 16968–16975.Google Scholar
  40. 40.
    Duan H, Dixit VM. RAIDD is a new 'death' adaptor molecule. Nature 1997; 385: 86–89.Google Scholar
  41. 41.
    Masumoto J, Zhou W, Chen FF, et al. Caspy, a zebrafish caspase, activated by ASC oligomerization is required for pharyngeal arch development. J Biol Chem 2003; 278: 4268–4276.Google Scholar
  42. 42.
    Bertin J, Nir WJ, Fischer CM, et al. Human CARD4 protein is a novel CED-4/Apaf-1 cell death family member that activates NF-kappaB. J Biol Chem 1999; 274: 12955–12958.Google Scholar
  43. 43.
    Srinivasula SM, Ahmad M, Lin JH, et al. CLAP, a novel caspase recruitment domain-containing protein in the tumor necrosis factor receptor pathway, regulates NF-kappaB activation and apoptosis. J Biol Chem 1999; 274: 17946–17954.Google Scholar
  44. 44.
    Inohara N, Koseki T, del Peso L, et al. Nod1, an Apaf-1-like activator of caspase-9 and nuclear factor-kappaB. J Biol Chem 1999; 274: 14560–14567.Google Scholar
  45. 45.
    Bertin J, Guo Y, Wang L, et al. CARD9 is a novel caspase recruitment domain-containing protein that interacts with BCL10/CLAP and activates NF-kappa B. J Biol Chem 2000; 275: 41082–41086.Google Scholar
  46. 46.
    Ogura Y, Inohara N, Benito A, Chen FF, Yamaoka S, Nunez G. Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-kappaB. J Biol Chem 2001; 276: 4812–4818.Google Scholar
  47. 47.
    Anonymous. Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. The International FMF Consortium. Cell 1997; 90: 797–807.Google Scholar
  48. 48.
    Hoffman HM, Wright FA, Broide DH, Wanderer AA, Kolodner RD. Identification of a locus on chromosome 1q44 for familial cold urticaria. Am J Hum Genet 2000; 66: 1693–1698.Google Scholar
  49. 49.
    Cuisset L, Drenth JP, Berthelot JM, et al. Genetic linkage of the Muckle-Wells syndrome to chromosome 1q44. Am J Hum Genet 1999; 65: 1054–1059.Google Scholar
  50. 50.
    Grenier JM, Wang L, Manji GA, et al. Functional screening of five PYPAF family members identifies PYPAF5 as a novel regulator of NF-kappaB and caspase-1. FEBS Lett 2002; 530: 73–78.Google Scholar
  51. 51.
    Tibbetts MD, Zheng L, Lenardo MJ. The death effector domain protein family: Regulators of cellular homeostasis. Nat Immunol 2003; 4: 404–409.Google Scholar
  52. 52.
    Hofmann K, Bucher P, Tschopp J. The CARD domain: A new apoptotic signalling motif. Trends Biochem Sci 1997; 22: 155–156.Google Scholar
  53. 53.
    McConnell BB, Vertino PM. Activation of a caspase-9-mediated apoptotic pathway by subcellular redistribution of the novel caspase recruitment domain protein TMS1. Cancer Res 2000; 60: 6243–6247.Google Scholar
  54. 54.
    Masumoto J, Taniguchi S, Sagara J. Pyrin N-terminal homology domain-and caspase recruitment domain-dependent oligomerization of ASC. Biochem Biophys Res Commun 2001; 280: 652–655.Google Scholar
  55. 55.
    Richards N, Schaner P, Diaz A, et al. Interaction between pyrin and the apoptotic speck protein (ASC) modulates ASC-induced apoptosis. J Biol Chem 2001; 276: 39320–39329.Google Scholar
  56. 56.
    Wang L, Manji GA, Grenier JM, et al. PYPAF7, a novel PYRIN-containing Apaf1-like protein that regulates activation of NF-kappa B and caspase-1-dependent cytokine processing. J Biol Chem 2002; 277: 29874–29880.Google Scholar
  57. 57.
    Garvey T, Bertin J, Siegel R, Lenardo M, Cohen J. The death effector domains (DEDs) of the molluscum contagiosum virus MC159 v-FLIP protein are not functionally interchangeable with each other or with the DEDs of caspase-8. Virology 2002; 300: 217–225.Google Scholar
  58. 58.
    Shearwin-Whyatt LM, Harvey NL, Kumar S. Subcellular localization and CARD-dependent oligomerization of the death adaptor RAIDD. Cell Death Differ 2000; 7: 155–165.Google Scholar
  59. 59.
    Lowe SW, Lin AW. Apoptosis in cancer. Carcinogenesis 2000; 21: 485–495.Google Scholar
  60. 60.
    Frisch SM, Ruoslahti E. Integrins and anoikis. Curr Opin Cell Biol 1997; 9: 701–706.Google Scholar
  61. 61.
    Geddes BJ, Wang L, Huang WJ, et al. Human CARD12 is a novel CED4/Apaf-1 family member that induces apoptosis. Biochem Biophys Res Commun 2001; 284: 77–82.Google Scholar
  62. 62.
    Masumoto J, Dowds TA, Schaner P, et al. ASC is an activating adaptor for NF-kappa B and caspase-8-dependent apoptosis. Biochem Biophys Res Commun 2003; 303: 69–73.Google Scholar
  63. 63.
    Dowds TA, Masumoto J, Chen FF, Ogura Y, Inohara N, Nunez G. Regulation of cryopyrin/Pypaf1 signaling by pyrin, the familial Mediterranean fever gene product. Biochem Biophys Res Commun 2003; 302: 575–580.Google Scholar
  64. 64.
    Ghosh S, May MJ, Kopp EB. NF-kappaB and Rel proteins: Evolutionarily conserved mediators of immune responses. Annu Rev Immunol 1998; 16: 225–260.Google Scholar
  65. 65.
    Karin M, Cao Y, Greten FR, Li ZW. NF-kappaB in cancer: from innocent bystander to major culprit. Nat Rev Cancer 2002; 2: 301–310.Google Scholar
  66. 66.
    Li Q, Verma IM. NF-kappaB regulation in the immune system. Nat Rev Immunol 2002; 2: 725–734.Google Scholar
  67. 67.
    Ghosh S, Karin M. Missing pieces in the NF-kappaB puzzle. Cell 2002; 109(Suppl): S81–96.Google Scholar
  68. 68.
    Stehlik C, Fiorentino L, Dorfleutner A, et al. The PAAD/PYRIN-family protein ASC is a dual regulator of a conserved step in nuclear factor kappaB activation pathways. J Exp Med 2002; 196: 1605–1615.Google Scholar
  69. 69.
    Zeuner A, Eramo A, Peschle C, De Maria R. Caspase activation without death. Cell Death Differ 1999; 6: 1075–1080.Google Scholar
  70. 70.
    Poyet JL, Srinivasula SM, Tnani M, Razmara M, Fernandes-Alnemri T, Alnemri ES. Identification of Ipaf, a human caspase-1-activating protein related to Apaf-1. J Biol Chem 2001; 276: 28309–28313.Google Scholar
  71. 71.
    Shiohara M, Taniguchi S, Masumoto J, et al. ASC, which is composed of a PYD and a CARD, is up-regulated by inflammation and apoptosis in human neutrophils. Biochem Biophys Res Commun 2002; 293: 1314–1318.Google Scholar
  72. 72.
    Chu ZL, Pio F, Xie Z, et al. A novel enhancer of the Apaf1 apoptosome involved in cytochrome c-dependent caspase activation and apoptosis. J Biol Chem 2001; 276: 9239–9245.Google Scholar
  73. 73.
    Hall PA, Coates PJ, Ansari B, Hopwood D. Regulation of cell number in the mammalian gastrointestinal tract: The importance of apoptosis. J Cell Sci 1994; 107: 3569–3577.Google Scholar
  74. 74.
    Hlaing T, Guo RF, Dilley KA, et al. Molecular cloning and characterization of DEFCAP-L and-S, two isoforms of a novel member of the mammalian Ced-4 family of apoptosis proteins. J Biol Chem 2001; 276: 9230–9238.Google Scholar

Copyright information

© Kluwer Academic Publishers 2004

Authors and Affiliations

  1. 1.Department of Radiation Oncology and Winship Cancer InstituteEmory University School of MedicineAtlantaUSA

Personalised recommendations