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) activity is necessary for the transformation phenotype of equine fibroblasts. Among the many changes induced by BPV-1, matrix metalloproteinase 1 (MMP-1) upregulation contributes to the invasiveness of equine fibroblasts. However, it is not yet known how BPV-1 proteins regulate equine MMP-1 expression. To elucidate this mechanism, the equine MMP-1 promoter was cloned and analysed. A putative activator protein-1 (AP-1)-binding site was demonstrated to be crucial for upregulated MMP-1 promoter activity by BPV-1. BPV-1 E6 and E7 proteins increased MMP-1 promoter activity, and inhibition of BPV-1 gene expression by small interfering RNA significantly reduced the promoter activity. c-Jun and Fra-1, two components of the AP-1 transcription factor complex, were overexpressed and activated by BPV-1 in equine fibroblasts. Finally, BPV-1 E5, E6 and E7 proteins increased MMP-1 mRNA and protein expression. In conclusion, the expression of MMP-1 can be enhanced by BPV-1 oncoproteins E6 and E7 through the AP-1 transcription factor and by E5 via an indirect mechanism. These findings shed light on the mechanism of BPV-1-mediated equine fibroblast infiltration and indicate that both BPV-1 oncoproteins and AP-1 could be potential targets for equine sarcoid therapy.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.033431-0
2011-11-01
2019-12-15
Loading full text...

Full text loading...

/deliver/fulltext/jgv/92/11/2608.html?itemId=/content/journal/jgv/10.1099/vir.0.033431-0&mimeType=html&fmt=ahah

References

  1. Akgül B., García-Escudero R., Ghali L., Pfister H. J., Fuchs P. G., Navsaria H., Storey A.. ( 2005; ). The E7 protein of cutaneous human papillomavirus type 8 causes invasion of human keratinocytes into the dermis in organotypic cultures of skin. . Cancer Res 65:, 2216–2223. [CrossRef] [PubMed]
    [Google Scholar]
  2. Angel P., Karin M.. ( 1991; ). The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation. . Biochim Biophys Acta 1072:, 129–157.[PubMed]
    [Google Scholar]
  3. 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]
  4. 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]
  5. Behren A., Simon C., Schwab R. M., Loetzsch E., Brodbeck S., Huber E., Stubenrauch F., Zenner H. P., Iftner T.. ( 2005; ). Papillomavirus E2 protein induces expression of the matrix metalloproteinase-9 via the extracellular signal-regulated kinase/activator protein-1 signaling pathway. . Cancer Res 65:, 11613–11621. [CrossRef] [PubMed]
    [Google Scholar]
  6. 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]
  7. Birkedal-Hansen H.. ( 1995; ). Proteolytic remodeling of extracellular matrix. . Curr Opin Cell Biol 7:, 728–735. [CrossRef] [PubMed]
    [Google Scholar]
  8. Borzacchiello G., Russo V., Gentile F., Roperto F., Venuti A., Nitsch L., Campo M. S., Roperto S.. ( 2006; ). Bovine papillomavirus E5 oncoprotein binds to the activated form of the platelet-derived growth factor β receptor in naturally occurring bovine urinary bladder tumours. . Oncogene 25:, 1251–1260. [CrossRef] [PubMed]
    [Google Scholar]
  9. Borzacchiello G., Russo V., Della Salda L., Roperto S., Roperto F.. ( 2008; ). Expression of platelet-derived growth factor-β receptor and bovine papillomavirus E5 and E7 oncoproteins in equine sarcoid. . J Comp Pathol 139:, 231–237. [CrossRef] [PubMed]
    [Google Scholar]
  10. 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]
  11. Burkhardt A., Willingham M., Gay C., Jeang K. T., Schlegel R.. ( 1989; ). The E5 oncoprotein of bovine papillomavirus is oriented asymmetrically in Golgi and plasma membranes. . Virology 170:, 334–339. [CrossRef] [PubMed]
    [Google Scholar]
  12. 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]
  13. Chinenov Y., Kerppola T. K.. ( 2001; ). Close encounters of many kinds: Fos–Jun interactions that mediate transcription regulatory specificity. . Oncogene 20:, 2438–2452. [CrossRef] [PubMed]
    [Google Scholar]
  14. Corteggio A., Di Geronimo O., Roperto S., Roperto F., Borzacchiello G.. ( 2011; ). Bovine papillomavirus E7 oncoprotein binds to p600 in naturally occurring equine sarcoids. . J Gen Virol 92:, 378–382. [CrossRef] [PubMed]
    [Google Scholar]
  15. Coussens L. M., Fingleton B., Matrisian L. M.. ( 2002; ). Matrix metalloproteinase inhibitors and cancer: trials and tribulations. . Science 295:, 2387–2392. [CrossRef] [PubMed]
    [Google Scholar]
  16. DeMasi J., Huh K. W., Nakatani Y., Münger K., Howley P. M.. ( 2005; ). Bovine papillomavirus E7 transformation function correlates with cellular p600 protein binding. . Proc Natl Acad Sci U S A 102:, 11486–11491. [CrossRef] [PubMed]
    [Google Scholar]
  17. DiMaio D., Mattoon D.. ( 2001; ). Mechanisms of cell transformation by papillomavirus E5 proteins. . Oncogene 20:, 7866–7873. [CrossRef] [PubMed]
    [Google Scholar]
  18. Duffy C. L., Phillips S. L., Klingelhutz A. J.. ( 2003; ). Microarray analysis identifies differentiation-associated genes regulated by human papillomavirus type 16 E6. . Virology 314:, 196–205. [CrossRef] [PubMed]
    [Google Scholar]
  19. Eferl R., Wagner E. F.. ( 2003; ). AP-1: a double-edged sword in tumorigenesis. . Nat Rev Cancer 3:, 859–868. [CrossRef] [PubMed]
    [Google Scholar]
  20. Garneau N. L., Wilusz J., Wilusz C. J.. ( 2007; ). The highways and byways of mRNA decay. . Nat Rev Mol Cell Biol 8:, 113–126. [CrossRef] [PubMed]
    [Google Scholar]
  21. Hirata M., Sato T., Tsumagari M., Shimada A., Nakano H., Hashizume K., Ito A.. ( 2003; ). Differential regulation of the expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases by cytokines and growth factors in bovine endometrial stromal cells and trophoblast cell line BT-1 in vitro. . Biol Reprod 68:, 1276–1281. [CrossRef] [PubMed]
    [Google Scholar]
  22. Huh K. W., DeMasi J., Ogawa H., Nakatani Y., Howley P. M., Münger K.. ( 2005; ). Association of the human papillomavirus type 16 E7 oncoprotein with the 600-kDa retinoblastoma protein-associated factor, p600. . Proc Natl Acad Sci U S A 102:, 11492–11497. [CrossRef] [PubMed]
    [Google Scholar]
  23. Jackson C.. ( 1936; ). The incidence and pathology of tumours of domestic animals in South Africa. . Ondesterpoort J Vet Res 6:, 378–385.
    [Google Scholar]
  24. Kähäri V. M., Saarialho-Kere U.. ( 1997; ). Matrix metalloproteinases in skin. . Exp Dermatol 6:, 199–213. [CrossRef] [PubMed]
    [Google Scholar]
  25. Karin M., Hawkins P. T.. ( 1996; ). The regulation of AP-1 activity by mitogen-activated protein kinases. . Philos Trans R Soc Lond B Biol Sci 351:, 127–134. [CrossRef] [PubMed]
    [Google Scholar]
  26. Karin M., Liu Z., Zandi E.. ( 1997; ). AP-1 function and regulation. . Curr Opin Cell Biol 9:, 240–246. [CrossRef] [PubMed]
    [Google Scholar]
  27. Knottenbelt D. C.. ( 2005; ). A suggested clinical classification of the equine sarcoid. . Clinical Techniques In Equine Practice 4:, 278–295. [CrossRef]
    [Google Scholar]
  28. Lavach J. D., Sullins K. E., Roberts S. M., Severin G. A., Wheeler C., Lueker D. C.. ( 1985; ). BCG treatment of periocular sarcoid. . Equine Vet J 17:, 445–448. [CrossRef] [PubMed]
    [Google Scholar]
  29. Leaner V. D., Chick J. F., Donninger H., Linniola I., Mendoza A., Khanna C., Birrer M. J.. ( 2009; ). Inhibition of AP-1 transcriptional activity blocks the migration, invasion, and experimental metastasis of murine osteosarcoma. . Am J Pathol 174:, 265–275. [CrossRef] [PubMed]
    [Google Scholar]
  30. Lichtinghagen R., Bahr M. J., Wehmeier M., Michels D., Haberkorn C. I., Arndt B., Flemming P., Manns M. P., Boeker K. H.. ( 2003; ). Expression and coordinated regulation of matrix metalloproteinases in chronic hepatitis C and hepatitis C virus-induced liver cirrhosis. . Clin Sci (Lond) 105:, 373–382. [CrossRef] [PubMed]
    [Google Scholar]
  31. Lin C. W., Georgescu H. I., Evans C. H.. ( 1993; ). The role of AP-1 in matrix metalloproteinase gene expression. . Agents Actions 39: (Suppl. 1), C215–C218. [CrossRef] [PubMed]
    [Google Scholar]
  32. 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]
  33. Malliri A., Symons M., Hennigan R. F., Hurlstone A. F., Lamb R. F., Wheeler T., Ozanne B. W.. ( 1998; ). The transcription factor AP-1 is required for EGF-induced activation of rho-like GTPases, cytoskeletal rearrangements, motility, and in vitro invasion of A431 cells. . J Cell Biol 143:, 1087–1099. [CrossRef] [PubMed]
    [Google Scholar]
  34. Martens A., De Moor A., Demeulemeester J., Peelman L.. ( 2001a; ). 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]
  35. Martens A., De Moor A., Ducatelle R.. ( 2001b; ). PCR detection of bovine papilloma virus DNA in superficial swabs and scrapings from equine sarcoids. . Vet J 161:, 280–286. [CrossRef] [PubMed]
    [Google Scholar]
  36. Matthews C. P., Colburn N. H., Young M. R.. ( 2007; ). AP-1 a target for cancer prevention. . Curr Cancer Drug Targets 7:, 317–324. [CrossRef] [PubMed]
    [Google Scholar]
  37. Neary K., DiMaio D.. ( 1989; ). Open reading frames E6 and E7 of bovine papillomavirus type 1 are both required for full transformation of mouse C127 cells. . J Virol 63:, 259–266.[PubMed]
    [Google Scholar]
  38. 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]
  39. 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]
  40. 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]
  41. Pagès G., Berra E., Milanini J., Levy A. P., Pouysségur J.. ( 2000; ). Stress-activated protein kinases (JNK and p38/HOG) are essential for vascular endothelial growth factor mRNA stability. . J Biol Chem 275:, 26484–26491. [CrossRef] [PubMed]
    [Google Scholar]
  42. 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]
  43. Pennie W. D., Grindlay G. J., Cairney M., Campo M. S.. ( 1993; ). Analysis of the transforming functions of bovine papillomavirus type 4. . Virology 193:, 614–620. [CrossRef] [PubMed]
    [Google Scholar]
  44. Pustovrh M. C., Jawerbaum A., Capobianco E., White V., Martínez N., López-Costa J. J., González E.. ( 2005; ). Oxidative stress promotes the increase of matrix metalloproteinases-2 and -9 activities in the feto-placental unit of diabetic rats. . Free Radic Res 39:, 1285–1293. [CrossRef] [PubMed]
    [Google Scholar]
  45. 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]
  46. Ragland K. W. L. III, Keown G. F. H., Spencer G. R.. ( 1970; ). Equine sarcoid. . Equine Vet J 2:, 2–11. [CrossRef]
    [Google Scholar]
  47. Sato H., Kita M., Seiki M.. ( 1993; ). v-Src activates the expression of 92-kDa type IV collagenase gene through the AP-1 site and the GT box homologous to retinoblastoma control elements. A mechanism regulating gene expression independent of that by inflammatory cytokines. . J Biol Chem 268:, 23460–23468.[PubMed]
    [Google Scholar]
  48. Shapiro S. D.. ( 1998; ). Matrix metalloproteinase degradation of extracellular matrix: biological consequences. . Curr Opin Cell Biol 10:, 602–608. [CrossRef] [PubMed]
    [Google Scholar]
  49. Shaulian E., Karin M.. ( 2002; ). AP-1 as a regulator of cell life and death. . Nat Cell Biol 4:, E131–E136. [CrossRef] [PubMed]
    [Google Scholar]
  50. Smeal T., Binetruy B., Mercola D. A., Birrer M., Karin M.. ( 1991; ). Oncogenic and transcriptional cooperation with Ha-Ras requires phosphorylation of c-Jun on serines 63 and 73. . Nature 354:, 494–496. [CrossRef] [PubMed]
    [Google Scholar]
  51. Surti T., Klein O., Aschheim K., DiMaio D., Smith S. O.. ( 1998; ). Structural models of the bovine papillomavirus E5 protein. . Proteins 33:, 601–612. [CrossRef] [PubMed]
    [Google Scholar]
  52. Tarwid J. N., Fretz P. B., Clark E. G.. ( 1985; ). Equine sarcoids: a study with emphasis on pathological diagnosis. . Compend Contin Educ Pract Vet 7:, 293–300.
    [Google Scholar]
  53. Urakami S., Tsuchiya H., Orimoto K., Kobayashi T., Igawa M., Hino O.. ( 1997; ). Overexpression of members of the AP-1 transcriptional factor family from an early stage of renal carcinogenesis and inhibition of cell growth by AP-1 gene antisense oligonucleotides in the Tsc2 gene mutant (Eker) rat model. . Biochem Biophys Res Commun 241:, 24–30. [CrossRef] [PubMed]
    [Google Scholar]
  54. Vogt P. K.. ( 2001; ). Jun, the oncoprotein. . Oncogene 20:, 2365–2377. [CrossRef] [PubMed]
    [Google Scholar]
  55. Westermarck J., Kähäri V. M.. ( 1999; ). Regulation of matrix metalloproteinase expression in tumor invasion. . FASEB J 13:, 781–792.[PubMed]
    [Google Scholar]
  56. 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]
  57. Yamamoto H., Itoh F., Senota A., Adachi Y., Yoshimoto M., Endoh T., Hinoda Y., Yachi A., Imai K.. ( 1995; ). Expression of matrix metalloproteinase matrilysin (MMP-7) was induced by activated Ki-ras via AP-1 activation in SW1417 colon cancer cells. . J Clin Lab Anal 9:, 297–301. [CrossRef] [PubMed]
    [Google Scholar]
  58. Yuan Z., Gallagher A., Gault E. A., Campo M. S., Nasir L.. ( 2007a; ). Bovine papillomavirus infection in equine sarcoids and in bovine bladder cancers. . Vet J 174:, 599–604. [CrossRef] [PubMed]
    [Google Scholar]
  59. Yuan Z., Philbey A. W., Gault E. A., Campo M. S., Nasir L.. ( 2007b; ). Detection of bovine papillomavirus type 1 genomes and viral gene expression in equine inflammatory skin conditions. . Virus Res 124:, 245–249. [CrossRef] [PubMed]
    [Google Scholar]
  60. Yuan Z. Q., Gault E. A., Gobeil P., Nixon C., Campo M. S., Nasir L.. ( 2008a; ). 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]
  61. Yuan Z. Q., Nicolson L., Marchetti B., Gault E. A., Campo M. S., Nasir L.. ( 2008b; ). Transcriptional changes induced by bovine papillomavirus type 1 in equine fibroblasts. . J Virol 82:, 6481–6491. [CrossRef] [PubMed]
    [Google Scholar]
  62. Yuan Z., Gobeil P. A., Campo M. S., Nasir L.. ( 2010a; ). Equine sarcoid fibroblasts over-express matrix metalloproteinases and are invasive. . Virology 396:, 143–151. [CrossRef] [PubMed]
    [Google Scholar]
  63. Yuan Z. Q., Bennett L., Campo M. S., Nasir L.. ( 2010b; ). 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]
  64. Yuan Z., Gault E. A., Campo M. S., Nasir L.. ( 2011a; ). Different contribution of bovine papillomavirus type 1 oncoproteins to the transformation of equine fibroblasts. . J Gen Virol 92:, 773–783. [CrossRef] [PubMed]
    [Google Scholar]
  65. Yuan Z., Gault E. A., Campo M. S., Nasir L.. ( 2011b; ). p38 mitogen-activated protein kinase is crucial for bovine papillomavirus type-1 transformation of equine fibroblasts. . J Gen Virol 92:, 1778–1786. [CrossRef]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.033431-0
Loading
/content/journal/jgv/10.1099/vir.0.033431-0
Loading

Data & Media loading...

Supplements

vol. , part 11, pp. 2608 - 2619

Nucleotide sequence of the 5'-flanking region of the equine MMP-1 gene

PCR primer sets used in this study [Single PDF file](106 KB)



PDF

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