1887

Abstract

Equine sarcoids represent the most common skin tumours in equids worldwide, characterized by extensive invasion and infiltration of lymphatics, rare regression and high recurrence after surgical intervention. Bovine papillomavirus type-1 (BPV-1) and less commonly BPV-2 are the causative agents of the diseases. It has been demonstrated that BPV-1 viral gene expression is necessary for maintaining the transformation phenotype. However, the underlying mechanism for BPV-1 transformation remains largely unknown, and the cellular factors involved in transformation are not fully understood. Previously mitogen-activated protein kinase (MAPK) signalling pathway has been shown to be important for cellular transformation. This study investigated the role of p38 MAPK (p38) in the transformation of equine fibroblasts by BPV-1. Elevated expression of phosphorylated p38 was observed in BPV-1 expressing fibroblasts due to the expression of BPV-1 E5 and E6. The phosphorylation of the MK2 kinase, a substrate of p38, was also enhanced. Inhibition of p38 activity by its selective inhibitor SB203580 changed cell morphology, reduced the proliferation of sarcoid fibroblasts and inhibited cellular invasiveness, indicating the indispensable role of p38 in BPV-1 transformation of equine fibroblasts. These findings provide new insights into the pathogenesis of equine sarcoids and suggest that p38 could be a potential target for equine sarcoid therapy.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.031526-0
2011-08-01
2019-12-09
Loading full text...

Full text loading...

/deliver/fulltext/jgv/92/8/1778.html?itemId=/content/journal/jgv/10.1099/vir.0.031526-0&mimeType=html&fmt=ahah

References

  1. Ashrafi G. H., Piuko K., Burden F., Yuan Z., Gault E. A., Müller M., Trawford A., Reid S. W., Nasir L., Campo M. S.. ( 2008;). Vaccination of sarcoid-bearing donkeys with chimeric virus-like particles of bovine papillomavirus type 1. . J Gen Virol 89:, 148–157. [CrossRef].[PubMed].
    [Google Scholar]
  2. Auble D. T., Sirum-Connolly K. L., Brinckerhoff C. E.. ( 1992;). Transcriptional regulation of matrix metalloproteinase genes: role of AP-1 sequences. . Matrix Suppl. 1:, 200.[PubMed].
    [Google Scholar]
  3. Behren A., Binder K., Vucelic G., Herberhold S., Hirt B., Loewenheim H., Preyer S., Zenner H. P., Simon C.. ( 2005;). The p38 SAPK pathway is required for Ha-ras induced in vitro invasion of NIH3T3 cells. . Exp Cell Res 303:, 321–330. [CrossRef].[PubMed].
    [Google Scholar]
  4. Benbow U., Brinckerhoff C. E.. ( 1997;). The AP-1 site and MMP gene regulation: what is all the fuss about?. Matrix Biol 15:, 519–526. [CrossRef].[PubMed].
    [Google Scholar]
  5. Boosani C. S., Nalabothula N., Munugalavadla V., Cosgrove D., Keshamoun V. G., Sheibani N., Sudhakar A.. ( 2009;). FAK and p38-MAP kinase-dependent activation of apoptosis and caspase-3 in retinal endothelial cells by alpha1(IV)NC1. . Invest Ophthalmol Vis Sci 50:, 4567–4575. [CrossRef].[PubMed].
    [Google Scholar]
  6. Borzacchiello G., Russo V., Della Salda L., Roperto S., Roperto F.. ( 2008;). Expression of platelet-derived growth factor-beta receptor and bovine papillomavirus E5 and E7 oncoproteins in equine sarcoid. . J Comp Pathol 139:, 231–237. [CrossRef].[PubMed].
    [Google Scholar]
  7. Borzacchiello G., Mogavero S., De Vita G., Roperto S., Della Salda L., Roperto F.. ( 2009;). Activated platelet-derived growth factor-β receptor expression, PI3K-AKT pathway molecular analysis, and transforming signals in equine sarcoids. . Vet Pathol 46:, 589–597. [CrossRef].[PubMed].
    [Google Scholar]
  8. Carr E. A., Théon A. P., Madewell B. R., Griffey S. M., Hitchcock M. E.. ( 2001;). Bovine papillomavirus DNA in neoplastic and nonneoplastic tissues obtained from horses with and without sarcoids in the western United States. . Am J Vet Res 62:, 741–744. [CrossRef].[PubMed].
    [Google Scholar]
  9. Chen W., Bowden G. T.. ( 1999;). Activation of p38 MAP kinase and ERK are required for ultraviolet-B induced c-fos gene expression in human keratinocytes. . Oncogene 18:, 7469–7476. [CrossRef].[PubMed].
    [Google Scholar]
  10. Crawford H. C., Matrisian L. M.. ( 1996;). Mechanisms controlling the transcription of matrix metalloproteinase genes in normal and neoplastic cells. . Enzyme Protein 49:, 20–37.[PubMed].
    [Google Scholar]
  11. Cuenda A., Rouse J., Doza Y. N., Meier R., Cohen P., Gallagher T. F., Young P. R., Lee J. C.. ( 1995;). SB 203580 is a specific inhibitor of a MAP kinase homologue which is stimulated by cellular stresses and interleukin-1. . FEBS Lett 364:, 229–233. [CrossRef].[PubMed].
    [Google Scholar]
  12. Eckert R. E., Sharief Y., Jones S. L.. ( 2009;). p38 mitogen-activated kinase (MAPK) is essential for equine neutrophil migration. . Vet Immunol Immunopathol 129:, 181–191. [CrossRef].[PubMed].
    [Google Scholar]
  13. Finlay M., Yuan Z., Burden F., Trawford A., Morgan I. M., Campo M. S., Nasir L.. ( 2009;). The detection of bovine papillomavirus type 1 DNA in flies. . Virus Res 144:, 315–317. [CrossRef].[PubMed].
    [Google Scholar]
  14. Goedert M., Cuenda A., Craxton M., Jakes R., Cohen P.. ( 1997;). Activation of the novel stress-activated protein kinase SAPK4 by cytokines and cellular stresses is mediated by SKK3 (MKK6); comparison of its substrate specificity with that of other SAP kinases. . EMBO J 16:, 3563–3571. [CrossRef].[PubMed].
    [Google Scholar]
  15. Hedges J. C., Dechert M. A., Yamboliev I. A., Martin J. L., Hickey E., Weber L. A., Gerthoffer W. T.. ( 1999;). A role for p38(MAPK)/HSP27 pathway in smooth muscle cell migration. . J Biol Chem 274:, 24211–24219. [CrossRef].[PubMed].
    [Google Scholar]
  16. Jackson C.. ( 1936;). The incidence and pathology of tumours of domestic animals in South Africa. . Ondesterpoort Journal of Veterinary Science and Animal Industry 6:, 378–385.
    [Google Scholar]
  17. Knottenbelt D. C.. ( 2005;). A suggested clinical classification of the equine sarcoid. . Clinical Techniques in Equine Practice 4:, 278–295. [CrossRef]
    [Google Scholar]
  18. Lee J. C., Laydon J. T., McDonnell P. C., Gallagher T. F., Kumar S., Green D., McNulty D., Blumenthal M. J., Keys J. R. et al. ( 1994;). A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. . Nature 372:, 739–746. [CrossRef].[PubMed].
    [Google Scholar]
  19. Loesch M., Zhi H. Y., Hou S. W., Qi X. M., Li R. S., Basir Z., Iftner T., Cuenda A., Chen G.. ( 2010;). p38γ MAPK cooperates with c-Jun in trans-activating matrix metalloproteinase 9. . J Biol Chem 285:, 15149–15158. [CrossRef].[PubMed].
    [Google Scholar]
  20. Marchetti B., Gault E. A., Cortese M. S., Yuan Z., Ellis S. A., Nasir L., Campo M. S.. ( 2009;). Bovine papillomavirus type 1 oncoprotein E5 inhibits equine MHC class I and interacts with equine MHC I heavy chain. . J Gen Virol 90:, 2865–2870. [CrossRef].[PubMed].
    [Google Scholar]
  21. Martens A., De Moor A., Demeulemeester J., Peelman L.. ( 2001;a). Polymerase chain reaction analysis of the surgical margins of equine sarcoids for bovine papilloma virus DNA. . Vet Surg 30:, 460–467. [CrossRef].[PubMed].
    [Google Scholar]
  22. Martens A., De Moor A., Ducatelle R.. ( 2001;b). PCR detection of bovine papilloma virus DNA in superficial swabs and scrapings from equine sarcoids. . Vet J 161:, 280–286. [CrossRef].[PubMed].
    [Google Scholar]
  23. Nasir L., Reid S. W.. ( 1999;). Bovine papillomaviral gene expression in equine sarcoid tumours. . Virus Res 61:, 171–175. [CrossRef].[PubMed].
    [Google Scholar]
  24. Nixon C., Chambers G., Ellsmore V., Campo M. S., Burr P., Argyle D. J., Reid S. W., Nasir L.. ( 2005;). Expression of cell cycle associated proteins cyclin A, CDK-2, p27kip1 and p53 in equine sarcoids. . Cancer Lett 221:, 237–245. [CrossRef].[PubMed].
    [Google Scholar]
  25. Otten N., von Tscharner C., Lazary S., Antczak D. F., Gerber H.. ( 1993;). DNA of bovine papillomavirus type 1 and 2 in equine sarcoids: PCR detection and direct sequencing. . Arch Virol 132:, 121–131. [CrossRef].[PubMed].
    [Google Scholar]
  26. Ozanne B. W., Spence H. J., McGarry L. C., Hennigan R. F.. ( 2007;). Transcription factors control invasion: AP-1 the first among equals. . Oncogene 26:, 1–10. [CrossRef].[PubMed].
    [Google Scholar]
  27. Pascoe R. R., Summers P. M.. ( 1981;). Clinical survey of tumours and tumour-like lesions in horses in south east Queensland. . Equine Vet J 13:, 235–239. [CrossRef].[PubMed].
    [Google Scholar]
  28. Piotrowicz R. S., Hickey E., Levin E. G.. ( 1998;). Heat shock protein 27 kDa expression and phosphorylation regulates endothelial cell migration. . FASEB J 12:, 1481–1490.[PubMed].
    [Google Scholar]
  29. Pyne N. J., Pyne S.. ( 1997;). Platelet-derived growth factor activates a mammalian Ste20 coupled mitogen-activated protein kinase in airway smooth muscle. . Cell Signal 9:, 311–317. [CrossRef].[PubMed].
    [Google Scholar]
  30. Ragland W. L., Spencer G. R.. ( 1969;). Attempts to relate bovine papilloma virus to the cause of equine sarcoid: equidae inoculated intradermally with bovine papilloma virus. . Am J Vet Res 30:, 743–752.[PubMed].
    [Google Scholar]
  31. Ragland K. W. L. III, Keown G. F. H., Spencer G. R.. ( 1970;). Equine sarcoid. . Equine Vet J 2:, 2–11. [CrossRef]
    [Google Scholar]
  32. Rouse J., Cohen P., Trigon S., Morange M., Alonso-Llamazares A., Zamanillo D., Hunt T., Nebreda A. R.. ( 1994;). A novel kinase cascade triggered by stress and heat shock that stimulates MAPKAP kinase-2 and phosphorylation of the small heat shock proteins. . Cell 78:, 1027–1037. [CrossRef].[PubMed].
    [Google Scholar]
  33. Rousseau S., Houle F., Landry J., Huot J.. ( 1997;). p38 MAP kinase activation by vascular endothelial growth factor mediates actin reorganization and cell migration in human endothelial cells. . Oncogene 15:, 2169–2177. [CrossRef].[PubMed].
    [Google Scholar]
  34. Simon C., Goepfert H., Boyd D.. ( 1998;). Inhibition of the p38 mitogen-activated protein kinase by SB 203580 blocks PMA-induced Mr 92,000 type IV collagenase secretion and in vitro invasion. . Cancer Res 58:, 1135–1139.[PubMed].
    [Google Scholar]
  35. Tangkijvanich P., Santiskulvong C., Melton A. C., Rozengurt E., Yee H. F. Jr. ( 2002;). p38 MAP kinase mediates platelet-derived growth factor-stimulated migration of hepatic myofibroblasts. . J Cell Physiol 191:, 351–361. [CrossRef].[PubMed].
    [Google Scholar]
  36. Tarwid J. N., Fretz P. B., Clark E. G.. ( 1985;). Equine sarcoids: a study with emphasis on pathological diagnosis. . The Compendium of Continuing Education 7:, 293–300.
    [Google Scholar]
  37. Yamaguchi H., Igarashi M., Hirata A., Sugae N., Tsuchiya H., Jimbu Y., Tominaga M., Kato T.. ( 2004;). Altered PDGF-BB-induced p38 MAP kinase activation in diabetic vascular smooth muscle cells: roles of protein kinase C-δ. . Arterioscler Thromb Vasc Biol 24:, 2095–2101. [CrossRef].[PubMed].
    [Google Scholar]
  38. Yuan Z. Q., Gault E. A., Gobeil P., Nixon C., Campo M. S., Nasir L.. ( 2008;a). Establishment and characterization of equine fibroblast cell lines transformed in vivo and in vitro by BPV-1: model systems for equine sarcoids. . Virology 373:, 352–361. [CrossRef].[PubMed].
    [Google Scholar]
  39. Yuan Z. Q., Nicolson L., Marchetti B., Gault E. A., Campo M. S., Nasir L.. ( 2008;b). Transcriptional changes induced by bovine papillomavirus type 1 in equine fibroblasts. . J Virol 82:, 6481–6491. [CrossRef].[PubMed].
    [Google Scholar]
  40. Yuan Z., Gobeil P. A., Campo M. S., Nasir L.. ( 2010;a). Equine sarcoid fibroblasts over-express matrix metalloproteinases and are invasive. . Virology 396:, 143–151. [CrossRef].[PubMed].
    [Google Scholar]
  41. Yuan Z. Q., Bennett L., Campo M. S., Nasir L.. ( 2010;b). Bovine papillomavirus type 1 E2 and E7 proteins down-regulate Toll like receptor 4 (TLR4) expression in equine fibroblasts. . Virus Res 149:, 124–127. [CrossRef].[PubMed].
    [Google Scholar]
  42. Yuan Z., Gault E. A., Campo M. S., Nasir L.. ( 2011;). Different contribution of bovine papillomavirus type 1 oncoproteins to the transformation of equine fibroblasts. . J Gen Virol 92:, 773–783. [CrossRef].[PubMed].
    [Google Scholar]
  43. Zarubin T., Han J.. ( 2005;). Activation and signaling of the p38 MAP kinase pathway. . Cell Res 15:, 11–18. [CrossRef].[PubMed].
    [Google Scholar]
  44. Zhao M., New L., Kravchenko V. V., Kato Y., Gram H., di Padova F., Olson E. N., Ulevitch R. J., Han J.. ( 1999;). Regulation of the MEF2 family of transcription factors by p38. . Mol Cell Biol 19:, 21–30.[PubMed].
    [Google Scholar]
  45. Zimmermann H., Koh C. H., Degenkolbe R., O’Connor M. J., Müller A., Steger G., Chen J. J., Lui Y., Androphy E., Bernard H. U.. ( 2000;). Interaction with CBP/p300 enables the bovine papillomavirus type 1 E6 oncoprotein to downregulate CBP/p300-mediated transactivation by p53. . J Gen Virol 81:, 2617–2623.[PubMed].
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.031526-0
Loading
/content/journal/jgv/10.1099/vir.0.031526-0
Loading

Data & Media loading...

Most Cited This Month

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error