Skip to main content
SpringerLink
Log in

TMS1/ASC: The cancer connection

  • Published:
Apoptosis Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  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. 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. 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. 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. Weber CH, Vincenz C. The death domain superfamily: A tale of two interfaces? Trends Biochem Sci 2001; 26: 475–481.

    Google Scholar 

  6. Martin SJ. Dealing the CARDs between life and death. Trends Cell Biol 2001; 11: 188–189.

    Google Scholar 

  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. 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. Kastner DL, O'Shea JJ. A fever gene comes in from the cold. Nat Genet 2001; 29: 241–242.

    Google Scholar 

  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. 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. 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. 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. 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. 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. 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. 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. 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. Bird AP. CpG-rich islands and the function of DNA methylation. Nature 1986; 321: 209–213.

    Google Scholar 

  20. Antequera F, Bird A. CpG islands. Exs 1993; 64: 169–185.

    Google Scholar 

  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. 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. Cross SH, Bird AP. CpG islands and genes. Curr Opin Genet Dev 1995; 5: 309–314.

    Google Scholar 

  24. Wigler M, Levy D, Perucho M. The somatic replication of DNA methylation. Cell 1981; 24: 33–40.

    Google Scholar 

  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. Jones PA, Laird PW. Cancer epigenetics comes of age. Nat Genet 1999; 21: 163–167.

    Google Scholar 

  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. Esteller M, Corn PG, Baylin SB, Herman JG. A gene hypermethylation profile of human cancer. Cancer Res 2001; 61: 3225–3229.

    Google Scholar 

  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. 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. 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. 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. 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. 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. Inohara N, Nunez G. NODs: Intracellular proteins involved in inflammation and apoptosis. Nat Rev Immunol 2003; 3: 371–382.

    Google Scholar 

  36. Deveraux QL, Reed JC. IAP family proteins-suppressors of apoptosis. Genes Dev 1999; 13: 239–252.

    Google Scholar 

  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. 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. 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. Duan H, Dixit VM. RAIDD is a new 'death' adaptor molecule. Nature 1997; 385: 86–89.

    Google Scholar 

  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. 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. 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. 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. 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. 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. 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.

  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. 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. 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. 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. Hofmann K, Bucher P, Tschopp J. The CARD domain: A new apoptotic signalling motif. Trends Biochem Sci 1997; 22: 155–156.

    Google Scholar 

  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. 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. 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. 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. 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. 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. Lowe SW, Lin AW. Apoptosis in cancer. Carcinogenesis 2000; 21: 485–495.

    Google Scholar 

  60. Frisch SM, Ruoslahti E. Integrins and anoikis. Curr Opin Cell Biol 1997; 9: 701–706.

    Google Scholar 

  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. 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. 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. 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. 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. Li Q, Verma IM. NF-kappaB regulation in the immune system. Nat Rev Immunol 2002; 2: 725–734.

    Google Scholar 

  67. Ghosh S, Karin M. Missing pieces in the NF-kappaB puzzle. Cell 2002; 109(Suppl): S81–96.

    Google Scholar 

  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. Zeuner A, Eramo A, Peschle C, De Maria R. Caspase activation without death. Cell Death Differ 1999; 6: 1075–1080.

    Google Scholar 

  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. 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. 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. 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. 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 

Download references

Author information

Authors and Affiliations

  1. Department of Radiation Oncology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, USA

    B. B. McConnell & P. M. Vertino

Authors
  1. B. B. McConnell
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. P. M. Vertino
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to P. M. Vertino.

Rights and permissions

Reprints and permissions

About this article

Cite this article

McConnell, B.B., Vertino, P.M. TMS1/ASC: The cancer connection. Apoptosis 9, 5–18 (2004). https://doi.org/10.1023/B:APPT.0000012117.32430.0c

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/B:APPT.0000012117.32430.0c

Search

Navigation