Skip to main content
PMC home page
The Journal of Cell Biology logoLink to The Journal of Cell Biology
. 1994 Feb 1;124(3):365–371. doi: 10.1083/jcb.124.3.365

HIV-1 transactivator protein Tat induces proliferation and TGF beta expression in human articular chondrocytes

PMCID: PMC2119928  PMID: 8294518

Abstract

The human immunodeficiency virus-1 (HIV-1) protein Tat binds to cell surface antigens and can regulate cellular responses. Tat has similar immunosuppressive effects as transforming growth factor-beta (TGF beta) and both inhibit lymphocyte proliferation. TGF beta is expressed by primary human articular chondrocytes and is their most potent growth factor. The present study analyzed the interactions of TGF beta and HIV Tat in the regulation of human articular chondrocytes. Synthetic or recombinant full-length Tat (1-86) induced chondrocyte proliferation and this was of similar magnitude as the response to TGF beta. Tat peptides that did not contain the RGD motif had similar chondrocyte stimulatory activity as full-length Tat. Among a series of Tat peptides, peptide 38-62 which contains the basic domain was the only one active, suggesting that this region is responsible for the effects on chondrocyte proliferation. Full-length Tat and peptide 38-62 synergized with TGF beta and induced proliferative responses that were greater than those obtained with any combination of the known chondrocyte growth factors. Further characterization of the interactions between Tat and TGF beta showed that Tat increased synthesis and TGF beta activity and TGF beta 1 mRNA levels. The stimulatory effects of Tat and peptide 38-62 on chondrocyte proliferation were reduced by neutralizing antibodies to TGF beta and by TGF beta antisense oligonucleotides. These results identify a virally encoded protein and a synthetic peptide derived from it as novel and potent chondrocyte growth stimuli which act at least in part through the induction of TGF beta.

Full Text

The Full Text of this article is available as a PDF (989.9 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Benya P. D., Shaffer J. D. Dedifferentiated chondrocytes reexpress the differentiated collagen phenotype when cultured in agarose gels. Cell. 1982 Aug;30(1):215–224. doi: 10.1016/0092-8674(82)90027-7. [DOI] [PubMed] [Google Scholar]
  2. Brake D. A., Debouck C., Biesecker G. Identification of an Arg-Gly-Asp (RGD) cell adhesion site in human immunodeficiency virus type 1 transactivation protein, tat. J Cell Biol. 1990 Sep;111(3):1275–1281. doi: 10.1083/jcb.111.3.1275. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Clark-Lewis I., Moser B., Walz A., Baggiolini M., Scott G. J., Aebersold R. Chemical synthesis, purification, and characterization of two inflammatory proteins, neutrophil activating peptide 1 (interleukin-8) and neutrophil activating peptide. Biochemistry. 1991 Mar 26;30(12):3128–3135. doi: 10.1021/bi00226a021. [DOI] [PubMed] [Google Scholar]
  4. Cullen B. R. Regulation of HIV-1 gene expression. FASEB J. 1991 Jul;5(10):2361–2368. doi: 10.1096/fasebj.5.10.1712325. [DOI] [PubMed] [Google Scholar]
  5. Delling U., Roy S., Sumner-Smith M., Barnett R., Reid L., Rosen C. A., Sonenberg N. The number of positively charged amino acids in the basic domain of Tat is critical for trans-activation and complex formation with TAR RNA. Proc Natl Acad Sci U S A. 1991 Jul 15;88(14):6234–6238. doi: 10.1073/pnas.88.14.6234. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Desai K., Loewenstein P. M., Green M. Isolation of a cellular protein that binds to the human immunodeficiency virus Tat protein and can potentiate transactivation of the viral promoter. Proc Natl Acad Sci U S A. 1991 Oct 15;88(20):8875–8879. doi: 10.1073/pnas.88.20.8875. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Ensoli B., Barillari G., Salahuddin S. Z., Gallo R. C., Wong-Staal F. Tat protein of HIV-1 stimulates growth of cells derived from Kaposi's sarcoma lesions of AIDS patients. Nature. 1990 May 3;345(6270):84–86. doi: 10.1038/345084a0. [DOI] [PubMed] [Google Scholar]
  8. Fisher A. G., Feinberg M. B., Josephs S. F., Harper M. E., Marselle L. M., Reyes G., Gonda M. A., Aldovini A., Debouk C., Gallo R. C. The trans-activator gene of HTLV-III is essential for virus replication. 1986 Mar 27-Apr 2Nature. 320(6060):367–371. doi: 10.1038/320367a0. [DOI] [PubMed] [Google Scholar]
  9. Frankel A. D. Activation of HIV transcription by Tat. Curr Opin Genet Dev. 1992 Apr;2(2):293–298. doi: 10.1016/s0959-437x(05)80287-4. [DOI] [PubMed] [Google Scholar]
  10. Frankel A. D., Pabo C. O. Cellular uptake of the tat protein from human immunodeficiency virus. Cell. 1988 Dec 23;55(6):1189–1193. doi: 10.1016/0092-8674(88)90263-2. [DOI] [PubMed] [Google Scholar]
  11. Helland D. E., Welles J. L., Caputo A., Haseltine W. A. Transcellular transactivation by the human immunodeficiency virus type 1 tat protein. J Virol. 1991 Aug;65(8):4547–4549. doi: 10.1128/jvi.65.8.4547-4549.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Howcroft T. K., Strebel K., Martin M. A., Singer D. S. Repression of MHC class I gene promoter activity by two-exon Tat of HIV. Science. 1993 May 28;260(5112):1320–1322. doi: 10.1126/science.8493575. [DOI] [PubMed] [Google Scholar]
  13. Jang K. L., Collins M. K., Latchman D. S. The human immunodeficiency virus tat protein increases the transcription of human Alu repeated sequences by increasing the activity of the cellular transcription factor TFIIIC. J Acquir Immune Defic Syndr. 1992;5(11):1142–1147. [PubMed] [Google Scholar]
  14. Jeyapaul J., Reddy M. R., Khan S. A. Activity of synthetic tat peptides in human immunodeficiency virus type 1 long terminal repeat-promoted transcription in a cell-free system. Proc Natl Acad Sci U S A. 1990 Sep;87(18):7030–7034. doi: 10.1073/pnas.87.18.7030. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Kamine J., Chinnadurai G. Synergistic activation of the human immunodeficiency virus type 1 promoter by the viral Tat protein and cellular transcription factor Sp1. J Virol. 1992 Jun;66(6):3932–3936. doi: 10.1128/jvi.66.6.3932-3936.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Kamine J., Subramanian T., Chinnadurai G. Sp1-dependent activation of a synthetic promoter by human immunodeficiency virus type 1 Tat protein. Proc Natl Acad Sci U S A. 1991 Oct 1;88(19):8510–8514. doi: 10.1073/pnas.88.19.8510. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Kato H., Sumimoto H., Pognonec P., Chen C. H., Rosen C. A., Roeder R. G. HIV-1 Tat acts as a processivity factor in vitro in conjunction with cellular elongation factors. Genes Dev. 1992 Apr;6(4):655–666. doi: 10.1101/gad.6.4.655. [DOI] [PubMed] [Google Scholar]
  18. Kekow J., Wachsman W., McCutchan J. A., Cronin M., Carson D. A., Lotz M. Transforming growth factor beta and noncytopathic mechanisms of immunodeficiency in human immunodeficiency virus infection. Proc Natl Acad Sci U S A. 1990 Nov;87(21):8321–8325. doi: 10.1073/pnas.87.21.8321. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Liu J., Perkins N. D., Schmid R. M., Nabel G. J. Specific NF-kappa B subunits act in concert with Tat to stimulate human immunodeficiency virus type 1 transcription. J Virol. 1992 Jun;66(6):3883–3887. doi: 10.1128/jvi.66.6.3883-3887.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Mann D. A., Frankel A. D. Endocytosis and targeting of exogenous HIV-1 Tat protein. EMBO J. 1991 Jul;10(7):1733–1739. doi: 10.1002/j.1460-2075.1991.tb07697.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Masuda T., Harada S. Modulation of host cell nuclear proteins that bind to HIV-1 trans-activation-responsive element RNA by phorbol ester. Virology. 1993 Feb;192(2):696–700. doi: 10.1006/viro.1993.1091. [DOI] [PubMed] [Google Scholar]
  22. Pocsik E., Higuchi M., Aggarwal B. B. Down-modulation of cell surface expression of p80 form of the tumor necrosis factor receptor by human immunodeficiency virus-1 tat gene. Lymphokine Cytokine Res. 1992 Dec;11(6):317–325. [PubMed] [Google Scholar]
  23. Puri R. K., Aggarwal B. B. Human immunodeficiency virus type 1 tat gene up-regulates interleukin 4 receptors on a human B-lymphoblastoid cell line. Cancer Res. 1992 Jul 1;52(13):3787–3790. [PubMed] [Google Scholar]
  24. Rosenthal A. K., Cheung H. S., Ryan L. M. Transforming growth factor beta 1 stimulates inorganic pyrophosphate elaboration by porcine cartilage. Arthritis Rheum. 1991 Jul;34(7):904–911. doi: 10.1002/art.1780340717. [DOI] [PubMed] [Google Scholar]
  25. Ruoslahti E. Integrins. J Clin Invest. 1991 Jan;87(1):1–5. doi: 10.1172/JCI114957. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Ruscetti F. W., Palladino M. A. Transforming growth factor-beta and the immune system. Prog Growth Factor Res. 1991;3(2):159–175. doi: 10.1016/s0955-2235(05)80006-7. [DOI] [PubMed] [Google Scholar]
  27. Sastry K. J., Reddy H. R., Pandita R., Totpal K., Aggarwal B. B. HIV-1 tat gene induces tumor necrosis factor-beta (lymphotoxin) in a human B-lymphoblastoid cell line. J Biol Chem. 1990 Nov 25;265(33):20091–20093. [PubMed] [Google Scholar]
  28. Selby M. J., Peterlin B. M. Trans-activation by HIV-1 Tat via a heterologous RNA binding protein. Cell. 1990 Aug 24;62(4):769–776. doi: 10.1016/0092-8674(90)90121-t. [DOI] [PubMed] [Google Scholar]
  29. Shibuya H., Irie K., Ninomiya-Tsuji J., Goebl M., Taniguchi T., Matsumoto K. New human gene encoding a positive modulator of HIV Tat-mediated transactivation. Nature. 1992 Jun 25;357(6380):700–702. doi: 10.1038/357700a0. [DOI] [PubMed] [Google Scholar]
  30. Taylor J. P., Cupp C., Diaz A., Chowdhury M., Khalili K., Jimenez S. A., Amini S. Activation of expression of genes coding for extracellular matrix proteins in Tat-producing glioblastoma cells. Proc Natl Acad Sci U S A. 1992 Oct 15;89(20):9617–9621. doi: 10.1073/pnas.89.20.9617. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Taylor J. P., Pomerantz R., Bagasra O., Chowdhury M., Rappaport J., Khalili K., Amini S. TAR-independent transactivation by Tat in cells derived from the CNS: a novel mechanism of HIV-1 gene regulation. EMBO J. 1992 Sep;11(9):3395–3403. doi: 10.1002/j.1460-2075.1992.tb05418.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Villiger P. M., Kusari A. B., ten Dijke P., Lotz M. IL-1 beta and IL-6 selectively induce transforming growth factor-beta isoforms in human articular chondrocytes. J Immunol. 1993 Sep 15;151(6):3337–3344. [PubMed] [Google Scholar]
  33. Villiger P. M., Lotz M. Differential expression of TGF beta isoforms by human articular chondrocytes in response to growth factors. J Cell Physiol. 1992 May;151(2):318–325. doi: 10.1002/jcp.1041510213. [DOI] [PubMed] [Google Scholar]
  34. Villiger P. M., Lotz M. Expression of prepro-enkephalin in human articular chondrocytes is linked to cell proliferation. EMBO J. 1992 Jan;11(1):135–143. doi: 10.1002/j.1460-2075.1992.tb05036.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Viscidi R. P., Mayur K., Lederman H. M., Frankel A. D. Inhibition of antigen-induced lymphocyte proliferation by Tat protein from HIV-1. Science. 1989 Dec 22;246(4937):1606–1608. doi: 10.1126/science.2556795. [DOI] [PubMed] [Google Scholar]
  36. Vogel B. E., Lee S. J., Hildebrand A., Craig W., Pierschbacher M. D., Wong-Staal F., Ruoslahti E. A novel integrin specificity exemplified by binding of the alpha v beta 5 integrin to the basic domain of the HIV Tat protein and vitronectin. J Cell Biol. 1993 Apr;121(2):461–468. doi: 10.1083/jcb.121.2.461. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Vogel J., Hinrichs S. H., Napolitano L. A., Ngo L., Jay G. Liver cancer in transgenic mice carrying the human immunodeficiency virus tat gene. Cancer Res. 1991 Dec 15;51(24):6686–6690. [PubMed] [Google Scholar]
  38. Vogel J., Hinrichs S. H., Reynolds R. K., Luciw P. A., Jay G. The HIV tat gene induces dermal lesions resembling Kaposi's sarcoma in transgenic mice. Nature. 1988 Oct 13;335(6191):606–611. doi: 10.1038/335606a0. [DOI] [PubMed] [Google Scholar]
  39. Weeks B. S., Desai K., Loewenstein P. M., Klotman M. E., Klotman P. E., Green M., Kleinman H. K. Identification of a novel cell attachment domain in the HIV-1 Tat protein and its 90-kDa cell surface binding protein. J Biol Chem. 1993 Mar 5;268(7):5279–5284. [PubMed] [Google Scholar]
  40. Zauli G., Davis B. R., Re M. C., Visani G., Furlini G., La Placa M. tat protein stimulates production of transforming growth factor-beta 1 by marrow macrophages: a potential mechanism for human immunodeficiency virus-1-induced hematopoietic suppression. Blood. 1992 Dec 15;80(12):3036–3043. [PubMed] [Google Scholar]

Articles from The Journal of Cell Biology are provided here courtesy of The Rockefeller University Press

RESOURCES