Molecular Mechanisms of the Effect of Herpesvirus saimiri Protein StpC on the Signaling Pathway Leading to NF-κB Activation

Abstract

Herpesvirus saimiri (Saimiriine herpesvirus-2) causes lethal T lymphoproliferative diseases in the susceptible species and transforms T lymphocytes to continuous growth in vitro. H. saimiri-induced transformation of T cells is becoming an important experimental tool of biomedical research. Two proteins of H. saimiri subgroup C, Tip and StpC, are essential for T cell transformation by this virus. It has been shown previously that StpC transforms fibroblasts, activates NF-κB, and binds to tumor necrosis factor (TNF)-receptor-associated factor (TRAF) proteins, but the molecular mechanism of its action remains insufficiently understood. This study further characterized the effect of StpC on NF-κB. First, StpC activates NF-κB via the consensus pathway involving activation of I-κB kinase and subsequent phosphorylation and degradation of I-κB in both T lymphoid and epithelial cells. Second, triggering of this pathway by StpC in both T lymphoid and epithelial cells is dependent on the presence of functional NF-κB-inducing kinase (NIK). Third, StpC physically interacts with TRAF in epithelial cells, and the effect of StpC on NF-κB activity in these cells requires the presence of functional TRAF. Finally the effect of StpC is completely independent of TNF-α, a well described stimulus of NF-κB activity. Moreover it appears that StpC uncouples stimulation of NF-κB activity from TNF-α stimulation. Overall these results argue that the effect of StpC on NF-κB is similar to the effects of other viral proteins, “usurping” the TRAF/NIK/I-κB kinase pathway, and reinforce the notion that the role of StpC in cell transformation by H. saimiri may be mediated by signaling that results in NF-κB activation. Herpesvirus saimiri (Saimiriine herpesvirus-2) causes lethal T lymphoproliferative diseases in the susceptible species and transforms T lymphocytes to continuous growth in vitro. H. saimiri-induced transformation of T cells is becoming an important experimental tool of biomedical research. Two proteins of H. saimiri subgroup C, Tip and StpC, are essential for T cell transformation by this virus. It has been shown previously that StpC transforms fibroblasts, activates NF-κB, and binds to tumor necrosis factor (TNF)-receptor-associated factor (TRAF) proteins, but the molecular mechanism of its action remains insufficiently understood. This study further characterized the effect of StpC on NF-κB. First, StpC activates NF-κB via the consensus pathway involving activation of I-κB kinase and subsequent phosphorylation and degradation of I-κB in both T lymphoid and epithelial cells. Second, triggering of this pathway by StpC in both T lymphoid and epithelial cells is dependent on the presence of functional NF-κB-inducing kinase (NIK). Third, StpC physically interacts with TRAF in epithelial cells, and the effect of StpC on NF-κB activity in these cells requires the presence of functional TRAF. Finally the effect of StpC is completely independent of TNF-α, a well described stimulus of NF-κB activity. Moreover it appears that StpC uncouples stimulation of NF-κB activity from TNF-α stimulation. Overall these results argue that the effect of StpC on NF-κB is similar to the effects of other viral proteins, “usurping” the TRAF/NIK/I-κB kinase pathway, and reinforce the notion that the role of StpC in cell transformation by H. saimiri may be mediated by signaling that results in NF-κB activation. Herpesvirus saimiri (Saimiriine herpesvirus-2) causes transformation of T lymphocytes, thus inducing lethal T lymphoproliferative diseases in the susceptible species. The strains of group C of this virus are capable of transforming human T cells in vitro (for reviews, see Refs. 1Broker B.M. Fickenscher H. Med. Microbiol. Immunol. 1999; 187: 127-136Google Scholar, 2Tsygankov A.Y. Romano G. Anticancer Res. 1999; 19: 973-983Google Scholar, 3Meinl E. Hohlfeld R. J. Neuroimmunol. 2000; 103: 1-7Google Scholar, 4Isakov N. Biesinger B. Eur. J. Biochem. 2000; 267: 3413-3421Google Scholar, 5Fickenscher H. Fleckenstein B. Philos. Trans. R. Soc. Lond. Ser. B Biol. Sci. 2001; 356: 545-567Google Scholar, 6Damania B. Jung J.U. Adv. Cancer Res. 2001; 80: 51-82Google Scholar). Although this transformation renders T cells capable of proliferating in a T cell antigen receptor/CD3 stimulation-independent manner similar to that of lymphoblastoid T cell lines, H. saimiri-transformed T cells retain their antigen-specific reactivity and growth dependence on interleukin-2 (7Broker B.M. Tsygankov A.Y. Muller-Fleckenstein I. Guse A.H. Chitaev N.A. Biesinger B. Fleckenstein B. Emmrich F. J. Immunol. 1993; 151: 1184-1192Google Scholar, 8Weber F. Meinl E. Drexler K. Czlonkowska A. Huber S. Fickenscher H. Muller-Fleckenstein I. Fleckenstein B. Wekerle H. Hohlfeld R. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 11049-11053Google Scholar). This property of H. saimiri-transformed T cells makes them a unique experimental tool of immunobiology (9Saha K. Sova P. Chao W. Chess L. Volsky D.J. Nat. Med. 1996; 2: 1272-1275Google Scholar, 10Vella C. Fickenscher H. Atkins C. Penny M. Daniels R. J. Gen. Virol. 1997; 78: 1405-1409Google Scholar, 11Saha K. Caruso M. Volsky D.J. Virology. 1997; 231: 1-9Google Scholar, 12Saadawi A.M. L'Faqihi F. Diab B.Y. Sol M.A. Enault G. Coppin H. Cantagrel A. Biesinger B. Fleckenstein B. Thomsen M. Tissue Antigens. 1997; 49: 431-437Google Scholar, 13Gallego M.D. Santamaria M. Pena J. Molina I.J. Blood. 1997; 90: 3089-3097Google Scholar, 14Saha K. Bentsman G. Chess L. Volsky D.J. J. Virol. 1998; 72: 876-881Google Scholar, 15Lacey S.F. Weinhold K.J. Chen C.H. McDanal C. Oei C. Greenberg M.L. AIDS Res. Hum. Retrovir. 1998; 14: 521-531Google Scholar, 16Martin-Villa J.M. Ferre-Lopez S. Lopez-Suarez J.C. Perez-Blas M. Castellano-Tortajada G. Sanchez-Gomez F. Arnaiz-Villena A. Tissue Antigens. 1998; 52: 430-434Google Scholar, 17Saha K. Volsky D.J. Matczak E. J. Virol. 1999; 73: 7891-7898Google Scholar, 18Henderson E.E. Tsygankov A.Y. Merlo J.J. Romano G. Guan M. Virology. 1999; 264: 125-133Google Scholar, 19Pecher G. Harnack U. Gunther M. Hummel M. Fichtner I. Schenk J.A. Biochem. Biophys. Res. Commun. 2001; 283: 738-742Google Scholar, 20Meinl E. Derfuss T. Pirzer R. Blank N. Lengenfelder D. Blancher A. Le Deist F. Fleckenstein B. Hivroz C. J. Biol. Chem. 2001; 276: 36902-36908Google Scholar, 21Nakamura H. Zarycki J. Sullivan J.L. Jung J.U. J. Immunol. 2001; 167: 2657-2665Google Scholar, 22Cabanillas J.A. Cambronero R. Pacheco-Castro A. Garcia-Rodirguez M.C. Martin-Fernandez J.M. Fontan G. Regueiro J.R. Clin. Exp. Immunol. 2002; 127: 366-373Google Scholar, 23Zheng N.N. Vella C. Easterbrook P.J. Daniels R.S. J. Gen. Virol. 2002; 83: 1343-1352Google Scholar, 24Vella C. Zheng N.N. Easterbrook P. Daniels R.S. AIDS Res. Hum. Retrovir. 2002; 18: 933-946Google Scholar). Two H. saimiri proteins, StpC and Tip, are essential for H. saimiri-mediated transformation of human T cells (25Medveczky M.M. Geck P. Sullivan J.L. Serbousek D. Djeu J.Y. Medveczky P.G. Virology. 1993; 196: 402-412Google Scholar, 26Duboise S.M. Guo J. Czajak S. Desrosiers R.C. Jung J.U. J. Virol. 1998; 72: 1308-1313Google Scholar). Tip has been shown to bind to Lck, a T cell-specific Src family protein-tyrosine kinase (PTK), 1The abbreviations used are: PTK, protein-tyrosine kinase; DMEM, Dulbecco's modified Eagle's medium; TNF, tumor necrosis factor; GST, glutathione S-transferase; ELISA, enzyme-linked immunosorbent assay; IKK, I-κB kinase; Stat, signal transducers and activators of transcription; TRAF, TNF-receptor-associated factor; SR, super-repressor; NIK, NF-κB-inducing kinase. 1The abbreviations used are: PTK, protein-tyrosine kinase; DMEM, Dulbecco's modified Eagle's medium; TNF, tumor necrosis factor; GST, glutathione S-transferase; ELISA, enzyme-linked immunosorbent assay; IKK, I-κB kinase; Stat, signal transducers and activators of transcription; TRAF, TNF-receptor-associated factor; SR, super-repressor; NIK, NF-κB-inducing kinase. and to become phosphorylated as a result (27Biesinger B. Tsygankov A.Y. Fickenscher H. Emmrich F. Fleckenstein B. B.M. J. Biol. Chem. Scholar, J.U. S.M. U. T. Desrosiers R.C. Biesinger B. J. Biol. Chem. Scholar, J.U. S.M. T. A. Desrosiers R.C. J. Virol. Scholar, N. Tsygankov A.Y. U. B. B.M. J. Biol. Chem. 1996; Scholar, T. Medveczky M.M. P.J. Medveczky P.G. J. Virol. 1996; Scholar, H. C. A. Biesinger B. Meinl E. B. Fleckenstein B. B.M. J. Virol. 1997; Scholar, Medveczky M.M. Medveczky P.G. J. Virol. 1999; 73: Scholar, Medveczky P.G. B.M. J. Biol. Chem. 1999; Scholar, K. Medveczky P.G. B.M. Virology. 2000; 276: Scholar, J. Biol. Chem. 2000; Scholar). It has been shown that Tip activates N. Tsygankov A.Y. U. B. B.M. J. Biol. Chem. 1996; Scholar, Medveczky M.M. Medveczky P.G. J. Virol. 1999; 73: Scholar, Medveczky P.G. B.M. J. Biol. Chem. 1999; Scholar, K. Medveczky P.G. B.M. Virology. 2000; 276: Scholar, T. Medveczky M. Medveczky P. J. Virol. 1997; Scholar, P. K. Medveczky P.G. B.M. Virology. 2002; and and Medveczky M.M. Medveczky P.G. J. Virol. 1999; 73: Scholar, J. Biol. Chem. 2000; Scholar, P. K. Medveczky P.G. B.M. Virology. 2002; Scholar, R. Medveczky M.M. R. Medveczky P.G. J. Virol. 1997; and factor of T cells K. Medveczky P.G. B.M. Virology. 2000; 276: Scholar, P. K. Medveczky P.G. B.M. Virology. 2002; Scholar, J.J. Tsygankov A.Y. Virology. 2001; Scholar). The role of StpC in H. saimiri-induced transformation is with the of StpC, is by its to J.U. J.J. Biesinger B. Fleckenstein Desrosiers R.C. Proc. Natl. Acad. Sci. U. S. A. Scholar). StpC has been shown to activation of NF-κB J.J. Tsygankov A.Y. Virology. 2001; Scholar, H. M. K. E. Jung J.U. J. Virol. 1999; 73: and J.U. Desrosiers R.C. Biol. Scholar). the of StpC to J.U. Desrosiers R.C. Virology. with its to bind to NF-κB H. M. K. E. Jung J.U. J. Virol. 1999; 73: and J.U. Desrosiers R.C. Biol. Scholar). it has been shown that H. saimiri a TRAF of StpC is of transforming human T lymphocytes H. M. K. E. Jung J.U. J. Virol. 1999; 73: Scholar). the of StpC and its role in T cell transformation is to be to the of StpC to NF-κB Finally the and of Tip StpC in T cells of human virus in these cells and their to human virus E.E. Tsygankov A.Y. Merlo J.J. Romano G. Guan M. Virology. 1999; 264: 125-133Google Scholar). results a that StpC may be used in the molecular the effects of StpC on signal are of for the of StpC and its It has been shown previously that StpC activates NF-κB in and epithelial cells H. M. K. E. Jung J.U. J. Virol. 1999; 73: Scholar). of StpC with TRAF proteins their in and similar epithelial cells has been H. M. K. E. Jung J.U. J. Virol. 1999; 73: Scholar). shown previously that StpC NF-κB activity in a T lymphoblastoid cell J.J. Tsygankov A.Y. Virology. 2001; Scholar). the effect of StpC on NF-κB in this by Tip, to NF-κB J.J. Tsygankov A.Y. Virology. 2001; Scholar). Although the effect of StpC on NF-κB activity is the consensus of these the molecular this effect insufficiently understood. The study on the of the effects of StpC on NF-κB activity. results that StpC activates NF-κB in T and cells by triggering the consensus TRAF/NIK/I-κB kinase pathway to I-κB phosphorylation and results argue that the effect of StpC on NF-κB is similar to of of human T cell and of virus (for reviews, see Refs. AIDS Res. Hum. Retrovir. 2000; Scholar, J. H. P. J. Clin. 2001; Scholar, M. Immunol. 2001; 19: and reinforce the notion that the role of StpC in cell transformation by H. saimiri may be mediated by signaling that results in NF-κB activation. cells from cell by them with a with the used as a with Tip, used with This has been described previously J.J. Romano G. G. E.E. Tsygankov A.Y. Anticancer Res. 1998; 18: Scholar). in with and and used for of lymphoblastoid cells and from them described previously J.J. Romano G. G. E.E. Tsygankov A.Y. Anticancer Res. 1998; 18: Scholar). cells in as described for of Tip StpC, of cells in with of the to the of of for to the cells with TNF-α for and by A. of The for the of by M. of for Src family described previously Tsygankov A.Y. J. Biol. Chem. 1998; Scholar). The human and by D. as described previously J. 2001; Scholar). The and for and and for and the to to the as a NF-κB and and the been described previously J.J. Tsygankov A.Y. Virology. 2001; Scholar). cells in a with of the NF-κB and of of for The cells The of activity the to NF-κB and activity from to the cell in a with an the NF-κB consensus from to the the to NF-κB and NF-κB to and by a to in an and and as described previously Tsygankov A.Y. J. Biol. Chem. 1998; Scholar). cells in in with and of with by to and with the to Tip and StpC described previously J.J. Romano G. G. E.E. Tsygankov A.Y. Anticancer Res. 1998; 18: Scholar). to NF-κB and and to from from with by an of with the by and cells from to bind the in The with and the of the with kinase cells in the and from cell with of the of and the in and with a of of kinase and of The on a for The by and the kinase The and the of cells an and to the cells the in and by and used to cells to functional and and of cells of cells by of as described previously J.J. Tsygankov A.Y. Virology. 2001; Scholar). cells in and and in and with for cells with a of for with and with to the cells. TNF-α to the cell cells and The of as described previously Tsygankov A.Y. J. Biol. Chem. 1998; Scholar). by and the with previously that of StpC NF-κB activity in T lymphoblastoid cells and that this effect by Tip of StpC and Tip a in interleukin-2 by cells J.J. Tsygankov A.Y. Virology. 2001; Scholar). signaling these effects and to their cell the of StpC and Tip on NF-κB activation in both lymphoblastoid and epithelial cells. StpC the NF-κB activity in Tip effect on NF-κB but the effect of StpC StpC NF-κB activity in cells, and Tip the effect of StpC, effect on its the of in the shown in the results cell with with cells to Tip StpC these results the that are by the of Tip StpC the effect of TNF-α, a consensus TNF-α shown to NF-κB in both and cells and cells, both and a in the NF-κB activity but to TNF-α and with TNF-α this and cells on the and and cells on the other these results that StpC the activity of NF-κB it from TNF-α stimulation. the mechanism of activation of NF-κB, the activation of NF-κB by StpC is to an in NF-κB activity in cells. of NF-κB to the an that StpC this in the of stimulation Tip effect on the of that of Tip and StpC this to as with that in the presence of StpC with NF-κB that the effects of Tip and StpC on NF-κB and Overall these results in with and described the effects of StpC and Tip on the of the activity of NF-κB to TNF-α similar to on the activity of NF-κB TNF-α activity of NF-κB and in cells Tip but in cells and of a is capable of the NF-κB and a and a of this with that both and activity of NF-κB The results with cells with previously in cells StpC the activity of NF-κB in cells as well J.J. Tsygankov A.Y. Virology. 2001; Scholar). further the effect of StpC on NF-κB the of NF-κB in the and the the of to the is a of NF-κB activation. that a of NF-κB is to the in cells in to the in and cells the of Tip and StpC in these in a of the of NF-κB the of StpC in cells results in with and NF-κB to the and an in its activity is by I-κB the effects of StpC and Tip on degradation in and cells. in the of in cells, in activation of NF-κB and a in the of by TNF-α in cells, Moreover the presence of StpC in with Tip the of TNF-α to a in the of in both and cells, in cells and Tip StpC in the of I-κB but NF-κB activation from TNF-α stimulation in a cell results a of the of degradation in the effect of StpC on NF-κB activity. this the effect of a capable of NF-κB activation by degradation of phosphorylated I-κB T. 78: Scholar, J. F. D. D. T. on the of StpC to the activity of NF-κB. a effect on NF-κB activity in cells StpC StpC with Tip further the notion that degradation is for activation of NF-κB, the of of cells Tip StpC in The of to NF-κB activation by its effect on NF-κB activity in and cells NF-κB is in cells, by the of both and of degradation activation of NF-κB in cells The results of I-κB degradation that this degradation essential for activation of NF-κB but in with the of effect of StpC on the of I-κB that this be by an in the of of I-κB is by NF-κB R. B. E. H. J. 1993; Scholar, M.L. T. D. 1993; to the effect of StpC on I-κB the effect of a on the of I-κB in cells Tip that in a of the in cells StpC but in Tip in cells This result that StpC a degradation of is by an I-κB further the effect of StpC on I-κB proteins of cells in and the of in and a the with this that the of in cells by StpC by the of Tip further the effect of StpC on phosphorylation of I-κB in cells Tip StpC in the of phosphorylation of in and cells and StpC a in I-κB phosphorylation in both cell and the of StpC and Tip this phosphorylation well in cells. the phosphorylation of I-κB is to IKK, the effect of StpC on activity kinase with a of to a of activity by StpC, from both and phosphorylation of in both and cells. further the the effects of StpC on NF-κB the of NIK, a kinase of in the NF-κB signaling pathway, to these The that an of this completely activation of NF-κB in both and cells and activation of NF-κB in cells used as a for the of as this activity. NF-κB to that in cells StpC Tip in and of in as for the the role of a of NF-κB that is to be in the activation of a of both and NF-κB activation in cells, NF-κB activity in these cells StpC of the effect of StpC on NF-κB but to a a of the of the of in to the of and in and that and further the role of and in the effects of StpC, of StpC with from the of cell StpC Tip, to for and StpC but with StpC from both and cells Overall the results of the that StpC activation of in cells that in I-κB phosphorylation and to an in I-κB degradation and NF-κB activation. NF-κB activation in experimental is by Tip the effect of StpC in both and cells to a the of study in cells, that this effect of Tip be dependent on J.J. Tsygankov A.Y. Virology. 2001; Scholar). cells Lck, and be in the effect of Tip in cells. This to the dependence of this effect of Tip in cells on cells with a of and an of Src family J. Biol. Chem. 1996; Scholar). NF-κB activity in cells in the manner as previously in cells J.J. Tsygankov A.Y. Virology. 2001; Scholar). Although NF-κB in cells, its effect as as that of NF-κB in cells that the effect of StpC independent of further the of cells with of Lck, a in NF-κB activity in and cells. This effect and dependent on the activity of it by by The in the effects of to their as by the effect of on NF-κB activity for the of Tip StpC in cells, Lck, to for for the effect of Tip on activation of NF-κB. that degradation activity by Tip in cells that Tip degradation of I-κB species other of that Tip StpC a effect on the of their this in cells This result that an in NF-κB activity by StpC is mediated by the of Tip to this effect of StpC may well result from the effect of Tip and StpC on This study the mechanism of activation of NF-κB. First, StpC activates NF-κB via the consensus pathway involving activation of and subsequent phosphorylation and degradation of I-κB in both T lymphoid and epithelial cells, thus the of cell Second, triggering of this pathway by StpC in both T lymphoid and epithelial cells is dependent on the presence of Third, results that StpC physically interacts with TRAF in epithelial cells and that the effect of StpC on NF-κB activity in these cells requires functional TRAF. Finally the effect of StpC is completely independent of TNF-α, a well described stimulus that NF-κB activity in a of cell Moreover StpC uncouples stimulation of NF-κB activity from TNF-α stimulation. This effect may be by the of by It is that the activation the of signaling the pathway further of this is on these and previously H. M. K. E. Jung J.U. J. Virol. 1999; 73: the that results in triggering of the pathway is to be of StpC to this pathway in cell 1998; Scholar, J.R. 2001; Scholar). The of signaling to NF-κB activation appears to be mediated by It is activation of is for the activation of NF-κB, but it is that the presence of is essential as a of this The of and to the NF-κB effect of StpC in T and cells. cells, both and activation of NF-κB by cells, activation of NF-κB, results are to of TRAF proteins cell-specific of NF-κB activation in epithelial and lymphoid cells. results in this study are with the notion that StpC activates NF-κB by triggering the consensus pathway, to degradation of I-κB and and of NF-κB by of the NF-κB and of the to the of StpC activates and phosphorylation of I-κB by of NF-κB, its to and the of of TRAF, NIK, and I-κB the effect of StpC on NF-κB activity. cells, a in NF-κB in the The to this result that the of degradation of in cells is to the activation of the degradation appears to be by a in is with activation of by NF-κB R. B. E. H. J. 1993; Scholar, M.L. T. D. 1993; Scholar). the of in cells remains it is that is for the of to with NF-κB the to NF-κB to the a the of NF-κB proteins be in cells, that in cells with the the that StpC activates NF-κB via the consensus pathway, a It has been shown that as activation of NF-κB via an pathway that phosphorylation of appears to of NF-κB and I-κB inducing degradation of I-κB A. C. D. B. P. 1996; Scholar, S. M. J.R. S. M. J. J. Immunol. 2000; Scholar, C. D. J. Biol. Chem. Scholar). I-κB by that I-κB phosphorylation in cells StpC with stimulation to the effect of StpC on NF-κB activity in cells, thus that phosphorylation is essential for this Overall argue that StpC activates NF-κB via the consensus signaling StpC signaling in the activation of NF-κB. the effect of StpC on signaling and activity that StpC, NF-κB, a effect on activity in cells StpC these result in the activation of effects of StpC on signaling be and J.J. Tsygankov A.Y. Virology. 2001; Scholar, H. M. K. E. Jung J.U. J. Virol. 1999; 73: results that in both T and cell Tip the effect of StpC on NF-κB NF-κB in the of The of effect of Tip on NF-κB in the of StpC is with the of Tip to to phosphorylation Moreover Tip the effect of StpC on activity the degradation of Tip the of the of by that of NF-κB activity is mediated by degradation but by that of It is important to that the in the activation of NF-κB the in the by StpC is similar to that by Tip the effects of StpC and Tip on NF-κB are the effect of Tip and StpC on a for the but of activation of NF-κB by Although the molecular mechanism by Tip the of requires further it is that Tip as an and thus phosphorylation of the that Tip the effect of StpC on phosphorylation activation of this It is that the effect of Tip the presence of Lck, a Src family protein-tyrosine kinase with Tip (27Biesinger B. Tsygankov A.Y. Fickenscher H. Emmrich F. Fleckenstein B. B.M. J. Biol. Chem. Scholar, J.U. S.M. U. T. Desrosiers R.C. Biesinger B. J. Biol. Chem. Tip the effect of StpC on NF-κB in cells, with other epithelial cells, the of Tip to NF-κB activation is independent of Lck, this kinase the effect of StpC on NF-κB in cells. The of the molecular of this effect of are First, the effect of is dependent on its kinase activity the of the NF-κB activation. Second, this effect of is functional Src for in the of of Lck, this kinase to the effect of StpC on NF-κB activity in cells to the of its in these and other epithelial cells. the previously effect of StpC on NF-κB activity in cells is to be by J.J. Tsygankov A.Y. Virology. 2001; Scholar). This notion is in with the of the NF-κB activity in and cells to the effect of StpC on NF-κB in cells is to a a Src it is by in cells J.J. Tsygankov A.Y. Virology. 2001; Scholar). Although both and J.J. Tsygankov A.Y. Virology. 2001; that Tip the activation of NF-κB in both and T lymphoid cells, the of this effect of Tip in its remains the effect of StpC on NF-κB activity is to that of StpC with Tip, Tip is capable of it It is that the role of Tip in H. saimiri-mediated transformation of T cells is to the activation of factor of T cells Medveczky M.M. Medveczky P.G. J. Virol. 1999; 73: Scholar, J. Biol. Chem. 2000; Scholar, P. K. Medveczky P.G. B.M. Virology. 2002; Scholar, R. Medveczky M.M. R. Medveczky P.G. J. Virol. 1997; the of of H. saimiri via the mechanism involving of in T cells J. J. Jung J.U. 2002; Scholar). the by Tip its its to the NF-κB further Overall the effect of StpC on NF-κB is similar to the effects of other viral proteins “usurping” the signaling pathway in NF-κB of human T cell of and of B virus (for reviews, see Refs. AIDS Res. Hum. Retrovir. 2000; Scholar, J. H. P. J. Clin. 2001; Scholar, M. Immunol. 2001; 19: Scholar). the molecular by StpC this pathway are of the effects of activates NF-κB by physically and with TRAF of this pathway E. E. G. Biol. 1996; and R. E. G. Proc. Natl. Acad. Sci. U. S. A. 1996; Scholar, and for a see J. H. P. J. Clin. 2001; Scholar). that NF-κB activation by and is to be essential for cell transformation by human T cell and S. H. M. T. M. T. M. J. 1996; Scholar, K. H. H. A. T. M. J. Virol. 1997; Scholar, Proc. Natl. Acad. Sci. U. S. A. 1997; Scholar, L. D. F. S. M. S. Virology. 1998; Scholar, M.D. L. J. Virol. 1999; 73: Scholar, G. 1999; 18: Scholar, B. C. L. Cancer Res. 2000; and the results NF-κB activation in cell transformation by H. saimiri H. M. K. E. Jung J.U. J. Virol. 1999; 73: Scholar, S. Jung J.U. J. Virol. 2000; study the notion that the role of StpC in cell transformation by H. saimiri may be mediated by its effect on the NF-κB It is that the of the pathway in the activation of NF-κB to the transformation of StpC further other effects of StpC, as its with J.U. Desrosiers R.C. Biol. may be the role of the pathway in the of StpC, in T cells StpC, in by H. are these cells the that may the to the of a signaling pathway in the of A. D. and M. for P. for the M. for with and G. for