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Gene Review

CrmA  -  Cytokine response modifier A, a serpin...

Cowpox virus

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Disease relevance of CrmA


High impact information on CrmA


Chemical compound and disease context of CrmA

  • CrmA (a serpin from cowpox virus) and zVAD-FMK (N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone) inhibited Sindbis virus-induced cell death, suggesting that cellular caspases facilitate apoptosis induced by Sindbis virus [9].
  • Human T leukemic cells engineered to overexpress the cowpox virus CrmA protein, a direct and specific inhibitor of caspase proteases, were studied for their resistance to 1-beta-D-arabinofurasosyl-cytosine (Ara-C), etoposide (VP-16), doxorubicin (DOX), and cis-dichlorodiammine platinum (CP) [10].
  • Overexpression of baculovirus protein p35 blocked ceramide-induced DNA fragmentation and proteolytic activity, whereas overexpression of cowpox virus protein CrmA had no effect on these events [11].

Biological context of CrmA


Anatomical context of CrmA

  • Thus, through CrmA, the virus may influence two of the pathways normally used to kill virus-infected cells: acting on endogenous proteinases such as ICE and on exogenous proteinases delivered by cytotoxic lymphocytes to infected cells [8].
  • Mixed infection of LLC-PK1 cells with wt RPV and wt CPV gave no PARP-cleaving activity, and all PARP cleavage mediated by SPI-2 and CrmA mutants of RPV and CPV, respectively, could be eliminated by coinfection with wt CPV [2].
  • In addition, overexpression of the cowpox virus protein CrmA, a molecule with inhibitory potential on caspase-1 and caspase-8, specifically involved in Fas-induced signaling, protected T cells from being destroyed by the neoplastic cells or the agonistic anti-Fas MoAb [16].
  • In U937 cells exposed to TPA, these proteolytic events can be inhibited by expression of a caspase-8 dominant negative mutant or the cowpox virus CrmA caspase inhibitor [17].
  • IL-3 withdrawal activates a CrmA-insensitive poly(ADP-ribose) polymerase cleavage enzyme in factor-dependent myeloid progenitor cells [15].

Associations of CrmA with chemical compounds

  • Altering the critical P1-aspartate in the CrmA reactive centre loop to alanine resulted in a virus (CPV-CrmA-D303A) that resembled CPV deleted for CrmA (CPVDeltaCrmA : : lacZ); on CAMs it produced white, inflammatory pocks with activated caspase-3 and reduced virus yields, suggesting that CrmA activities are mediated via proteinase inhibition [1].
  • Previously we have shown CrmA to be an inhibitor of the cysteine proteinase interleukin-1 beta-converting enzyme (ICE) [8].
  • In addition to CrmA, a tripeptide caspase-protease inhibitor, z-Val-Ala-Asp-fluoromethylketone could also suppress TGF-beta-induced apoptosis in a dose-dependent manner [18].
  • Although such cells were completely resistant to apoptosis induced by antibodies to the Apo-1/Fas surface receptor (a form of apoptosis known to be inhibitable by CrmA), they were not protected from ceramide-induced cell death [19].

Analytical, diagnostic and therapeutic context of CrmA

  • These results indicate that CrmA is an effective gene product for inhibiting Fas/FasL-mediated apoptosis, which suggests the potential therapeutic use of its gene transduction to protect against graft damage due to delayed and/or chronic xenograft rejection [20].
  • These data suggested that FasL and CrmA may be potent genes to prolong rat liver allograft survival [21].
  • Using the high responder rat combination of DA (RT-1(a)) donor to LEW (RT-1(1)) recipient, we performed orthotopic liver transplantation with subsequent delivery of adenoviral vectors containing FasL, CrmA, or LacZ, at a dose of 1 x 10(9) pfu via a recipient tail vein using a Cre-mediated gene expression system [21].


  1. Cowpox virus CrmA, Myxoma virus SERP2 and baculovirus P35 are not functionally interchangeable caspase inhibitors in poxvirus infections. Nathaniel, R., MacNeill, A.L., Wang, Y.X., Turner, P.C., Moyer, R.W. J. Gen. Virol. (2004) [Pubmed]
  2. Activation of caspases in pig kidney cells infected with wild-type and CrmA/SPI-2 mutants of cowpox and rabbitpox viruses. Macen, J., Takahashi, A., Moon, K.B., Nathaniel, R., Turner, P.C., Moyer, R.W. J. Virol. (1998) [Pubmed]
  3. Intracellular mechanisms of TRAIL: apoptosis through mitochondrial-dependent and -independent pathways. Suliman, A., Lam, A., Datta, R., Srivastava, R.K. Oncogene (2001) [Pubmed]
  4. Construction of multiple-epitope tag sequence by PCR for sensitive Western blot analysis. Nakajima, K., Yaoita, Y. Nucleic Acids Res. (1997) [Pubmed]
  5. Tumor necrosis factor-induced apoptosis is mediated by a CrmA-sensitive cell death pathway. Miura, M., Friedlander, R.M., Yuan, J. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  6. Target protease specificity of the viral serpin CrmA. Analysis of five caspases. Zhou, Q., Snipas, S., Orth, K., Muzio, M., Dixit, V.M., Salvesen, G.S. J. Biol. Chem. (1997) [Pubmed]
  7. Fas- and tumor necrosis factor-induced apoptosis is inhibited by the poxvirus crmA gene product. Tewari, M., Dixit, V.M. J. Biol. Chem. (1995) [Pubmed]
  8. Granzyme B is inhibited by the cowpox virus serpin cytokine response modifier A. Quan, L.T., Caputo, A., Bleackley, R.C., Pickup, D.J., Salvesen, G.S. J. Biol. Chem. (1995) [Pubmed]
  9. Sindbis virus induces apoptosis through a caspase-dependent, CrmA-sensitive pathway. Nava, V.E., Rosen, A., Veliuona, M.A., Clem, R.J., Levine, B., Hardwick, J.M. J. Virol. (1998) [Pubmed]
  10. Inhibition of caspase proteases by CrmA enhances the resistance of human leukemic cells to multiple chemotherapeutic agents. Antoku, K., Liu, Z., Johnson, D.E. Leukemia (1997) [Pubmed]
  11. Involvement of a CrmA-insensitive ICE/Ced-3-like protease in ceramide-induced apoptosis. Kojima, H., Datta, R. Oncol. Res. (1996) [Pubmed]
  12. Myxoma virus Serp2 is a weak inhibitor of granzyme B and interleukin-1beta-converting enzyme in vitro and unlike CrmA cannot block apoptosis in cowpox virus-infected cells. Turner, P.C., Sancho, M.C., Thoennes, S.R., Caputo, A., Bleackley, R.C., Moyer, R.W. J. Virol. (1999) [Pubmed]
  13. Subcellular localization of CrmA: identification of a novel leucine-rich nuclear export signal conserved in anti-apoptotic serpins. Rodriguez, J.A., Span, S.W., Kruyt, F.A., Giaccone, G. Biochem. J. (2003) [Pubmed]
  14. CrmA, a poxvirus-encoded serpin, inhibits cytotoxic T-lymphocyte-mediated apoptosis. Tewari, M., Telford, W.G., Miller, R.A., Dixit, V.M. J. Biol. Chem. (1995) [Pubmed]
  15. IL-3 withdrawal activates a CrmA-insensitive poly(ADP-ribose) polymerase cleavage enzyme in factor-dependent myeloid progenitor cells. Antoku, K., Liu, Z., Johnson, D.E. Leukemia (1998) [Pubmed]
  16. Constitutive expression of Fas (Apo-1/CD95) ligand on multiple myeloma cells: a potential mechanism of tumor-induced suppression of immune surveillance. Villunger, A., Egle, A., Marschitz, I., Kos, M., Böck, G., Ludwig, H., Geley, S., Kofler, R., Greil, R. Blood (1997) [Pubmed]
  17. Identification of proteins cleaved downstream of caspase activation in monocytes undergoing macrophage differentiation. Cathelin, S., Rébé, C., Haddaoui, L., Simioni, N., Verdier, F., Fontenay, M., Launay, S., Mayeux, P., Solary, E. J. Biol. Chem. (2006) [Pubmed]
  18. Involvement of caspase family proteases in transforming growth factor-beta-induced apoptosis. Chen, R.H., Chang, T.Y. Cell Growth Differ. (1997) [Pubmed]
  19. Ceramides induce a form of apoptosis in human acute lymphoblastic leukemia cells that is inhibited by Bcl-2, but not by CrmA. Geley, S., Hartmann, B.L., Kofler, R. FEBS Lett. (1997) [Pubmed]
  20. In vitro prevention of cell-mediated xeno-graft rejection via the Fas/FasL-pathway in CrmA-transducted porcine kidney cells. Fujino, M., Li, X.K., Suda, T., Hashimoto, M., Okabe, K., Yaginuma, H., Mikoshiba, K., Guo, L., Okuyama, T., Enosawa, S., Amemiya, H., Amano, T., Suzuki, S. Xenotransplantation (2001) [Pubmed]
  21. Exogenous Expression of Fas-Ligand or CrmA Prolongs the Survival in Rat Liver Transplantation. Adachi, K., Fujino, M., Kitazawa, Y., Funeshima-Fuji, N., Takahara, S., Kimura, H., Li, X.K. Transplant. Proc. (2006) [Pubmed]
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