Regulation of Fas-Ligand Expression during Activation-induced Cell Death in T Lymphocytes via Nuclear Factor κB

T cell receptor engagement activates transcription factors important for cytokine gene regulation. Additionally, this signaling pathway also leads to activation-induced apoptosis in T lymphocytes that is dependent on FasL transcription and expression. Here we demonstrate that nuclear factor κB (NF-κB), which is involved in the transcriptional regulation of many cytokine genes expressed in activated lymphocytes, also plays a role in T cell activation-induced FasL expression. Inhibition of NF-κB activity in a T cell hybridoma leads to decreased FasL expression and apoptosis upon T cell receptor stimulation. We identified the NF-κB site in the FasL promoter that contributes to such regulation. Co-expression of p65 (Rel A) with the FasL promoter enhanced its activity, and co-expression of IκB dramatically inhibited the inducible promoter activity. In contrast, the transcription factor AP-1 is not required for activation-induced FasL promoter activity. These results define a role for NF-κB in mediating FasL expression during T cell activation. T cell receptor engagement activates transcription factors important for cytokine gene regulation. Additionally, this signaling pathway also leads to activation-induced apoptosis in T lymphocytes that is dependent on FasL transcription and expression. Here we demonstrate that nuclear factor κB (NF-κB), which is involved in the transcriptional regulation of many cytokine genes expressed in activated lymphocytes, also plays a role in T cell activation-induced FasL expression. Inhibition of NF-κB activity in a T cell hybridoma leads to decreased FasL expression and apoptosis upon T cell receptor stimulation. We identified the NF-κB site in the FasL promoter that contributes to such regulation. Co-expression of p65 (Rel A) with the FasL promoter enhanced its activity, and co-expression of IκB dramatically inhibited the inducible promoter activity. In contrast, the transcription factor AP-1 is not required for activation-induced FasL promoter activity. These results define a role for NF-κB in mediating FasL expression during T cell activation. Activation-induced cell death (AICD) 1The abbreviations used are: AICD, activation-induced cell death; IL-2, interleukin 2; TCR, T cell receptor; NF-AT, nuclear factor of activated T cells; NF-κB, nuclear factor κB; PMA, phorbol myristate acetate; RT-PCR, reverse transcription-polymerase chain reaction; kbp, kilobase pair(s); bp, base pair(s); hFasL, human FasL; DN-MEKK, dominant negative mitogen-activated protein kinase kinase. is a major mechanism to maintain immune homeostasis. AICD occurs in mature T lymphocytes to limit antigen-specific responses. Upon clearing antigens and/or pathogens from the host, activated T cells are deleted via the activation of apoptosis, which we and others have shown to be dependent upon Fas ligand (FasL, CD95 ligand) expression and ligation of its receptor, Fas (CD95) (1Brunner T. Yoo N.J. LaFace D. Ware C.F. Green D.R. Int. Immunol. 1996; 9: 1017-1026Crossref Scopus (103) Google Scholar, 2Brunner T. Mogil R.J. LaFace D. Yoo N.J. Mahboubi A. Echeverri F. Martin S.J. Force W.R. Lynch D.H. Ware C.F. Green D.R. Nature. 1995; 373: 441-444Crossref PubMed Scopus (1272) Google Scholar, 3Alderson M.R. Tough T.W. Davis-Smith T. Braddy S. Falk B. Schooley K.A. Goodwin R.G. Smith C.A. Ramsdell F. Lynch D.H. J. Exp. Med. 1995; 181: 71-77Crossref PubMed Scopus (868) Google Scholar, 4Dhein J. Walczak H. Baumler C. Debatin K.-M. Krammer P.H. Nature. 1995; 373: 438-441Crossref PubMed Scopus (1607) Google Scholar, 5Ju S.-T. Panka D.J. Cui H. Ettinger R. El-Khatib M. Sherr D.H. Stanger B.Z. Marshak-Rothstein A. Nature. 1995; 373: 444-448Crossref PubMed Scopus (1453) Google Scholar). However, despite our understanding of the importance of FasL in controlling homeostasis, little is known about its transcriptional regulation. T cell receptor ligation activates a cascade of signaling events which leads to the activation of several transcription factors that regulate cytokine gene expression including interleukin-2 (IL-2) (6Weiss A. Littman D.R. Cell. 1994; 76: 263-274Abstract Full Text PDF PubMed Scopus (1955) Google Scholar). Signaling events post-TCR ligation and phospholipase C-γ1 lead to two distinct signals: activation of the protein kinase C pathway and release of intracellular Ca2+ stores, subsequent Ca2+influx, and the activation of the serine phosphatase, calcineurin (7Clipstone N.A. Crabtree G.R. Nature. 1992; 357: 695-697Crossref PubMed Scopus (1476) Google Scholar). These two signals can be mimicked by treatment of cells with the pharmacological agents phorbol myristate acetate and ionomycin. Calcineurin-mediated activation of the nuclear factor of activated T cells (NF-AT) and its role in cytokine gene expression is well established (7Clipstone N.A. Crabtree G.R. Nature. 1992; 357: 695-697Crossref PubMed Scopus (1476) Google Scholar, 8Rao A. Immunol. Today. 1994; 15: 274-281Abstract Full Text PDF PubMed Scopus (490) Google Scholar, 9Rothenberg E.V. Ward S.B. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 9358Crossref PubMed Scopus (169) Google Scholar), and more recently it was shown that NF-AT sites in the FasL promoter are important for T cell activation-induced FasL expression (10Latinis K. Norian L.A. Eliason S.L. Koretzky G.A. J. Biol. Chem. 1997; 272: 31427-31434Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar). Like NF-AT, nuclear factor κB (NF-κB) is also involved in the transcriptional regulation of the interleukin 2α receptor (11Bohnlein E. Lowenthal J.W. Siekewitz M. Ballard D.W. Franza B.R. Greene W.C. Cell. 1988; 53: 827-836Abstract Full Text PDF PubMed Scopus (248) Google Scholar) and the IL-2 genes (12Shibuya H. Yoneyama M. Taniguchi T. Int. Immunol. 1989; 1: 43-49Crossref PubMed Scopus (37) Google Scholar). NF-κB is present in the cytoplasm as two major precursor forms either as a RelA·p50 complex with the inhibiting IκB or as a heterodimeric RelA·p105 complex (13Baeuerle P.A. Henkel T. Annu. Rev. Immunol. 1994; 12: 141-179Crossref PubMed Scopus (4598) Google Scholar). Release of the RelA-p50 from its inhibitor, IκB, is dependent on the phosphorylation of IκB (14Baldwin A.S. Annu. Rev. Immunol. 1996; 14: 649-681Crossref PubMed Scopus (5578) Google Scholar), and recently, the kinases that phosphorylate IκB have been identified (15Mercurio F. Zhu H. Murray B.W. Shevchenko A. Bennett B.L. Li J. Young D.B. Barbosa M. Mann M. Manning A. Rao A. Science. 1997; 278: 860-866Crossref PubMed Scopus (1853) Google Scholar). NF-κB is then translocated into the nucleus as active heterodimers consisting of Rel A (p65), Rel B, and c-Rel, which regulate gene expression. Recently, we identified a role for NF-κB and another transcription factor, AP-1, in the regulation of stress-induced FasL expression (16Kasibhatla S. Brunner S. Genestier G. Echeverri E. Mahboubi A. Green D.R. Mol. Cell. 1998; 1: 543-551Abstract Full Text Full Text PDF PubMed Scopus (668) Google Scholar). In the present study, we sought to determine whether NF-κB and AP-1 regulate FasL expression in lymphocytes activated through the T cell receptor. Human leukemic Jurkat cells (ATCC) and Jurkat cells stably transfected with SV40 large T antigen were used in this study. The T cell hybridoma A1.1 has been described previously (2Brunner T. Mogil R.J. LaFace D. Yoo N.J. Mahboubi A. Echeverri F. Martin S.J. Force W.R. Lynch D.H. Ware C.F. Green D.R. Nature. 1995; 373: 441-444Crossref PubMed Scopus (1272) Google Scholar). All cells were grown in RPMI 1640 medium containing 10% fetal calf serum, 2 mml-glutamine, and 100 units/ml each penicillin and streptomycin (complete medium). Phorbol myristate acetate (PMA) was purchased from Sigma, and ionomycin was purchased from Calbiochem. Mouse anti-human CD3 (OKT3) antibody and hamster anti-mouse CD3ε (145–2C11) were purified from culture supernatants by protein A affinity chromatography. Anti-p65(RelA) antibody was purchased from Santa Cruz Biotechnology, Inc. (Santa Cruz, CA). All experiments were performed in 96-well plates and in triplicates samples, with cells resuspended at 0.5–1 × 106/ml in complete medium. For T cell receptor stimulation, 96-well plates were precoated with anti-CD3 antibody (2C11) in 50 mm Tris, pH 9.0. PMA and ionomycin were added at concentrations of 50 ng/ml and 0.5 μg/ml, respectively. The expression of Fas-L was determined by RT of total RNA followed by reverse PCR analysis (RT-PCR) as described previously (16Kasibhatla S. Brunner S. Genestier G. Echeverri E. Mahboubi A. Green D.R. Mol. Cell. 1998; 1: 543-551Abstract Full Text Full Text PDF PubMed Scopus (668) Google Scholar). Briefly, cDNAs were synthesized by extension of dT primers with 200 units of SuperScript II reverse transcriptase (Life Technologies, Inc.) in a mixture containing 1 μg of total RNA digested by RNase-free DNase (2 units/μg of RNA) (Ambion) for 15 min at 37 °C. PCR of the cDNA was performed in a final volume of 50 μl, containing all four dNTPs, 2 mm MgCl2, 2.5 units of AmpliTag (Life Technologies, Inc.), and each primer at 0.2 μm using the geneAmp 2400 PCR system (Perkin-Elmer). Amplification of β-actin served as control for sample loading and integrity. The following primers were designed to discriminate between the amplification of cDNA (low size PCR products) and contaminating genomic cDNA (high size PCR products): hFasL forward: TAAAACCGTTTGCTGGGGC. hFasL reverse: CTCAGCTCCTTTTTTTCAGGGG. β-Actin forward: TGACGGGGTCACCCACACTGTGCCCATCTA. β-Actin reverse: CTAGAAGCATTTGCGGTGGACGATGGAGGG. Cloning of the 1.2-kb FasL promoter and generation of the truncated version was described before (16Kasibhatla S. Brunner S. Genestier G. Echeverri E. Mahboubi A. Green D.R. Mol. Cell. 1998; 1: 543-551Abstract Full Text Full Text PDF PubMed Scopus (668) Google Scholar). A 1.2- and a 0.9-kb fragment of the hFasL promoter were subsequently used in the experiments described here. Jurkat T cells containing stably transfected SV40 large T antigen were electroporated as described previously (17Kasibhatla S. Nalefski E. Rao A. J. Immunol. 1993; 151: 3140-3151PubMed Google Scholar). Briefly, 1.5–2 × 107 cells were washed twice with serum-free RPMI 1640 medium, resuspended in 500 μl of the same medium, and transferred to 4-mm gap electroporation cuvettes (Bio-Rad). 20–60 μg of FasL or with IκB, or expression J. F. M. Mol. Cell. Biol. 1996; 15: Google Scholar, F. J. C. M. 1993; PubMed Scopus Google Scholar) were added to the cells and was at and in a Briefly, hFasL promoter were transfected with or co-expression was used to the in the cells were activated with PMA and ionomycin and for another were washed with and in 100 μl of the was by and the was used in the using a (16Kasibhatla S. Brunner S. Genestier G. Echeverri E. Mahboubi A. Green D.R. Mol. Cell. 1998; 1: 543-551Abstract Full Text Full Text PDF PubMed Scopus (668) Google Scholar). were for min at in a containing 50 mm pH mm MgCl2, 0.5 mm mm 500 mm and The used were consisting of the NF-κB site from the human FasL and the NF-κB from Santa Cruz Biotechnology, Inc. was with kinase (Life Technologies, Inc.) and and the were then to The were on a in In nuclear from Jurkat cells were as described (16Kasibhatla S. Brunner S. Genestier G. Echeverri E. Mahboubi A. Green D.R. Mol. Cell. 1998; 1: 543-551Abstract Full Text Full Text PDF PubMed Scopus (668) Google Scholar). μg of nuclear and 2 μg of in the has been that NF-κB is required for activation-induced cell death in T Recently, it was shown that activation-induced cell death by NF-κB and FasL expression M. M. J. S. K. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). we have recently shown that NF-κB is required for stress-induced FasL expression and apoptosis in T cells (16Kasibhatla S. Brunner S. Genestier G. Echeverri E. Mahboubi A. Green D.R. Mol. Cell. 1998; 1: 543-551Abstract Full Text Full Text PDF PubMed Scopus (668) Google Scholar). In contrast, by and others have that NF-κB can as of apoptosis by D. Martin S. T. Green D. Science. 1996; PubMed Scopus Google Scholar, A. D. Science. 1996; PubMed Scopus Google Scholar, M. A. Science. 1996; PubMed Scopus Google Scholar, H. D. M. Cell. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). We sought to determine whether of NF-κB can activation-induced cell death in T this we a recently described of NF-κB of a the nuclear of the NF-κB T. U. K. J. E. Cell. 1992; Full Text PDF PubMed Scopus Google Scholar). has been shown to the nuclear of the NF-κB S. R. T. J. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar). We the of the NF-κB or a control in activation-induced cell death in a T cell The T cell hybridoma A1.1 expression of FasL and apoptosis with cell receptor (1Brunner T. Yoo N.J. LaFace D. Ware C.F. Green D.R. Int. Immunol. 1996; 9: 1017-1026Crossref Scopus (103) Google Scholar). We a in apoptosis in the of the NF-κB and not the control 1 We then FasL expression by in cells and a in the of FasL 1 results that NF-κB be important of activation-induced FasL expression and subsequent cell Activation-induced cell death is by regulation of expression. T cell receptor and agents signals also FasL expression T. Yoo N.J. Green D.R. 1997; Scholar). are sites for several transcription factors in the 1.2-kb promoter of Fas ligand the results in 1 and to the T cell FasL we used a 1.2-kb FasL promoter (16Kasibhatla S. Brunner S. Genestier G. Echeverri E. Mahboubi A. Green D.R. Mol. Cell. 1998; 1: 543-551Abstract Full Text Full Text PDF PubMed Scopus (668) Google Scholar) and whether this is activated upon shown in 2 B, the 1.2-kb FasL promoter was activated upon of the receptor with anti-CD3 antibody as well as upon with the agents PMA and ionomycin. results were in using a FasL (10Latinis K. Norian L.A. Eliason S.L. Koretzky G.A. J. Biol. Chem. 1997; 272: 31427-31434Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar). the that this inducible transcription of the 1.2-kb FasL we then the of a 0.9-kb FasL 2 A) that has its In the shown in 2 we that T cells were activated with PMA and FasL activity of the 0.9-kb promoter was that of the 1.2-kb the role of NF-κB in AICD, we the of a NF-κB two of the κB C. M. J. Biol. 1995; PubMed Scopus Google Scholar) and that NF-κB is activated upon with PMA and ionomycin A in the site this activity We have previously shown that the NF-κB site to NF-κB from nuclear with the (16Kasibhatla S. Brunner S. Genestier G. Echeverri E. Mahboubi A. Green D.R. Mol. Cell. 1998; 1: 543-551Abstract Full Text Full Text PDF PubMed Scopus (668) Google Scholar). treatment with PMA and we then nuclear for NF-κB activity by using the NF-κB site from the FasL promoter (16Kasibhatla S. Brunner S. Genestier G. Echeverri E. Mahboubi A. Green D.R. Mol. Cell. 1998; 1: 543-551Abstract Full Text Full Text PDF PubMed Scopus (668) Google Scholar). shown in B, T cell activation NF-κB in The to this site was by the NF-κB M. D. Cell. 1989; Full Text PDF PubMed Scopus Google Scholar) and by antibody J. Mol. Cell. Biol. 1998; PubMed Scopus Google Scholar) not by control The of complex by antibody also that p65 is of the complex by PMA and ionomycin using of signaling R. E. T. 1997; Scopus Google Scholar) and have that NF-κB be involved in activation-induced cell death M. M. J. S. K. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, M. J. Immunol. 1996; Google Scholar). The experiments in that NF-κB is required for activation-induced cell death and FasL expression. We the that NF-κB T cell FasL on the of NF-κB activation on the of IκB, we the of inhibiting NF-κB activation using IκB or a D. Martin S. T. Green D. Science. 1996; PubMed Scopus Google Scholar). We Jurkat cells with the FasL with either IκB or the D. Martin S. T. Green D. Science. 1996; PubMed Scopus Google Scholar). shown in either of IκB the activity as well as activation of the FasL promoter with PMA and ionomycin. We have recently identified NF-κB in the FasL promoter for stress-induced promoter activity (16Kasibhatla S. Brunner S. Genestier G. Echeverri E. Mahboubi A. Green D.R. Mol. Cell. 1998; 1: 543-551Abstract Full Text Full Text PDF PubMed Scopus (668) Google Scholar). the importance of this NF-κB site in activation-induced FasL promoter we used a in which this site was (16Kasibhatla S. Brunner S. Genestier G. Echeverri E. Mahboubi A. Green D.R. Mol. Cell. 1998; 1: 543-551Abstract Full Text Full Text PDF PubMed Scopus (668) Google Scholar) and for its to be upon T cell activation. shown in B, the NF-κB site a on T cell FasL the that NF-κB is required for activation of the FasL The of the to through either or be a mechanism regulation by this of is has been shown that the p65 of NF-κB can as a transcriptional D. E. H. S. B. Greene Proc. Natl. Acad. Sci. U. S. A. 1992; PubMed Scopus Google Scholar). Co-expression of p65 (Rel A) with the FasL FasL activity and enhanced the of PMA and ionomycin to this promoter The NF-κB also the of this promoter to be by co-expression of the p65 of NF-κB of p65 was to expression of the Fas ligand gene in Jurkat cells as by PCR These a role for NF-κB in the FasL promoter following T cell activation. Recently, (10Latinis K. Norian L.A. Eliason S.L. Koretzky G.A. J. Biol. 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Echeverri E. Mahboubi A. Green D.R. Mol. Cell. 1998; 1: 543-551Abstract Full Text Full Text PDF PubMed Scopus (668) Google Scholar), inhibited stress-induced FasL activity We then whether the AP-1 site (16Kasibhatla S. Brunner S. Genestier G. Echeverri E. Mahboubi A. Green D.R. Mol. Cell. 1998; 1: 543-551Abstract Full Text Full Text PDF PubMed Scopus (668) Google Scholar) was required for FasL shown in B, a in the AP-1 site not FasL activity in to T cell receptor the of a signaling We have previously that this the of the promoter to agents (16Kasibhatla S. Brunner S. Genestier G. Echeverri E. Mahboubi A. Green D.R. Mol. Cell. 1998; 1: 543-551Abstract Full Text Full Text PDF PubMed Scopus (668) Google Scholar). engagement and activation leads to and as well as apoptosis in T cells (6Weiss A. Littman D.R. Cell. 1994; 76: 263-274Abstract Full Text PDF PubMed Scopus (1955) Google Scholar). of the signaling events lead to activation of AP-1, NF-κB, as well as the NF-AT of transcription factors E.V. Ward S.B. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 9358Crossref PubMed Scopus (169) Google Scholar), which are known to cytokine gene A of in the several has our understanding of this complex cytokine gene regulation. is also that transcription can a role in involved in forms of apoptosis, such as activation-induced cell death in T Activation-induced cell death is by in mature T lymphocytes (2Brunner T. Mogil R.J. LaFace D. Yoo N.J. Mahboubi A. Echeverri F. Martin S.J. Force W.R. Lynch D.H. Ware C.F. Green D.R. Nature. 1995; 373: 441-444Crossref PubMed Scopus (1272) Google Scholar, 3Alderson M.R. Tough T.W. Davis-Smith T. Braddy S. Falk B. Schooley K.A. Goodwin R.G. Smith C.A. Ramsdell F. Lynch D.H. J. Exp. Med. 1995; 181: 71-77Crossref PubMed Scopus (868) Google Scholar). (10Latinis K. Norian L.A. Eliason S.L. Koretzky G.A. J. Biol. Chem. 1997; 272: 31427-31434Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar) that NF-AT activation-induced FasL promoter activity. we recently that the transcription factors AP-1 and NF-κB regulate and stress-induced FasL expression (16Kasibhatla S. Brunner S. Genestier G. Echeverri E. Mahboubi A. Green D.R. Mol. Cell. 1998; 1: 543-551Abstract Full Text Full Text PDF PubMed Scopus (668) Google Scholar). we have that NF-κB also plays a role in T cell FasL expression. We that the regulation of the 1.2-kb FasL was dependent on NF-κB and that inhibiting NF-κB into the nucleus also inhibited FasL expression and apoptosis in T NF-κB was identified as a expressed protein that can a complex with a site in the chain R. D. Cell. Full Text PDF PubMed Scopus Google Scholar). was to also in T cell IL-2 and receptor genes (11Bohnlein E. Lowenthal J.W. Siekewitz M. Ballard D.W. Franza B.R. Greene W.C. Cell. 1988; 53: 827-836Abstract Full Text PDF PubMed Scopus (248) Google Scholar). is also that NF-κB can be involved in activation-induced cell death M. M. J. S. K. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, R. E. T. 1997; Scopus Google Scholar). AICD has been shown to be inhibited by M. M. J. S. K. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, M. J. Immunol. 1996; Google Scholar) and of activity such as K. S. Cui H. S. E. J. Immunol. 1997; PubMed Scopus Google Scholar, H. K. S. S. R. E. S.-T. Proc. Natl. Acad. Sci. U. S. A. 1997; PubMed Scopus Google Scholar). was recently shown that NF-κB activation and that IκB not NF-κB activation also cell death in T agents that or NF-κB activation to have on Inhibition of NF-κB also the of to FasL expression in T cells M. M. J. S. K. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). be involved in T cell we also the of inhibiting NF-κB in cell death and that inhibiting NF-κB this of apoptosis not NF-κB has also been in signaling events that cell death by the cytokine factor T. 1995; Full Text PDF PubMed Scopus Google Scholar). We and others previously that of NF-κB in Jurkat and cell cells to apoptosis D. Martin S. T. Green D. Science. 1996; PubMed Scopus Google Scholar). We have recently shown that the of NF-κB also and stress-induced apoptosis in Jurkat cells (16Kasibhatla S. Brunner S. Genestier G. Echeverri E. Mahboubi A. Green D.R. Mol. Cell. 1998; 1: 543-551Abstract Full Text Full Text PDF PubMed Scopus (668) Google Scholar). with the results described in this NF-κB to by Fas not activation of NF-κB G. K. A. R. R. Science. 1997; PubMed Scopus Google Scholar). the and ligand) apoptosis and also NF-κB S. Schooley K. C. J. G. Smith T. C. Smith C. 1995; Full Text PDF PubMed Scopus Google Scholar, M. A. A. Murray J. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, M. J. Smith C. Goodwin R. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, M. K. K. T. J. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). Like is also upon and its expression is inhibited by a role for calcineurin and NF-AT S. Krammer J. Immunol. 1998; PubMed Scopus Google Scholar). NF-κB also expression is not is that in T of the signals define gene expression. present also about the complex regulation of Fas A fragment of the FasL activity upon 1 a was shown to be for activity (10Latinis K. Norian L.A. Eliason S.L. Koretzky G.A. J. Biol. Chem. 1997; 272: 31427-31434Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar). is that be in the Fas ligand promoter that as of this A on human FasL promoter has the of a between in the promoter C. A. A. C. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). the between and in the the of a between and in this and also be another between the and the of the We are the promoter for such is also that NF-AT is to a FasL promoter (10Latinis K. Norian L.A. Eliason S.L. Koretzky G.A. J. Biol. Chem. 1997; 272: 31427-31434Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar), in the of a 1.2-kb a in the NF-AT site not the promoter activity. In contrast, a in the NF-κB site a on activation-induced Fas ligand promoter activity that NF-κB is for FasL expression. NF-κB, AP-1, and NF-AT are the transcription factors shown to be involved in forms of apoptosis, of which NF-κB to distinct the of this with to this is and signaling events on the same factor also on a cell have to regulate We the importance of the previously identified AP-1 site (16Kasibhatla S. Brunner S. Genestier G. Echeverri E. Mahboubi A. Green D.R. Mol. Cell. 1998; 1: 543-551Abstract Full Text Full Text PDF PubMed Scopus (668) Google Scholar) in T cell FasL expression and that AP-1 was for this of was required for by (16Kasibhatla S. Brunner S. Genestier G. Echeverri E. Mahboubi A. Green D.R. Mol. Cell. 1998; 1: 543-551Abstract Full Text Full Text PDF PubMed Scopus (668) Google Scholar). that the of transcription factors to regulate gene transcription with the of cell activation. The transcription factors AP-1 and NF-κB are involved in stress-induced FasL NF-AT and NF-κB to in T cell FasL expression.