The Regulation of CD95 (Fas) Ligand Expression in Primary T Cells: Induction of Promoter Activation in CD95LP-Luc Transgenic Mice

Norian, Lyse A.; Latinis, Kevin M.; Eliason, Steve; Lysoń, Krzysztof; Yang, Chunmei; Ratliff, Timothy L.; Koretzky, Gary A.

doi:10.4049/jimmunol.164.9.4471

Cited by 17 publications

(12 citation statements)

References 55 publications

(68 reference statements)

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“…Indeed, induced expression of TNFSF6 at the cell surface of activated T lymphocytes is inhibited by cyclosporin A, an inhibitor of the calcineurin phosphatase implicated in the regulation of NF-AT transcription factor activity and expression (29). The generation of transgenic mice in which the TNFSF6 promoter sequence controls the expression of a reporter gene evidenced a similar pattern of expression of the transgene and the endogenous gene in primary T lymphocytes, underscoring the role of these 5Ј-regulatory regions in TNFSF6 expression (30). Post-translational control of TNFSF6 expression has also been described.…”

mentioning

confidence: 86%

Active Transcription of the Human FASL/CD95L/TNFSF6 Promoter Region in T Lymphocytes Involves Chromatin Remodeling

Castellano

Vire

Pion

et al. 2006

Journal of Biological Chemistry

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Fas ligand (FasL/CD95L/TNFSF6), a member of the tumor necrosis factor family, initiates apoptosis in lymphoid and nonlymphoid tissues by binding to its receptor Fas (CD95/TNFRSF6). Although the transcriptional control of TNFSF6 gene expression is subjected to intense study, the role of its chromatin organization and accessibility to the transcriptional machinery is not known. Here, we determined the chromatin organization of TNFSF6 gene 5 regulatory regions. Using the indirect end-labeling technique, a unique region named HSS1 and encompassing nucleotides ؊189 to ؉185 according to the transcriptional start site, was identified throughout a 20-kilobase nucleosomal DNA domain surrounding the promoter. The HSS1 region displayed hypersensitivity to in vivo DNase I digestion in TNFSF6-expressing cells only, including upon T cell activation. Hypersensitivity to micrococcal nuclease digestion and to specific restriction enzyme digestion suggested the precise positioning of two nucleosomes across the transcription start site and minimal promoter region, likely interfering with TNFSF6 active transcription in T lymphocytes. Indeed, HSS1 hypersensitivity to nuclease digestion strictly correlated with TNFSF6 transcription, including in primary and leukemia T cells. HSS1 chromatin remodeling preceded detectable TNFSF6 mRNA accumulation and was blocked by cycloheximide that also prevented TNFSF6 transcription. However, DNA methylation levels of the TNFSF6 HSS1 region did not correlate with transcriptional activation. Induction of global protein acetylation by treatment with histone deacetylase inhibitors was not accompanied by HSS1 chromatin remodeling and/or TNFSF6 transcription. We conclude that chromatin remodeling is a primary event in the activation of TNFSF6 expression in primary and leukemia T cells and that mechanisms independent of protein deacetylation and of DNA methylation of the TNFSF6 promoter region are involved in the repression of TNFSF6 gene expression.The TNFSF family related members are type II transmembrane proteins. Besides of their role in many important biological processes such as development, organogenesis, immunity, cell death, and survival, TNFSFs are implicated in various acquired or genetic human diseases ranging from septic shock to autoimmune disorders, allograft rejection, viral infections, and cancer (1). Hence, various therapeutic approaches aim to target these molecules, and there has been much interest toward the elucidation of the molecular mechanisms controlling their expression. TNFSF family member expression is contextually dependent on the nature, differentiation, activation, and cell cycle status of producing tissues. The regulated expression of the TNFSF genes implicates not only transcriptional but also post-transcriptional and post-translational mechanisms, together ensuring appropriate spatiotemporal expression. Escape of this tightly controlled expression has been described in various pathological conditions, including viral infections or neoplasm.TNFSF6 (FasL/CD95L) is a key pl...

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mentioning

confidence: 86%

Active Transcription of the Human FASL/CD95L/TNFSF6 Promoter Region in T Lymphocytes Involves Chromatin Remodeling

Castellano

Vire

Pion

et al. 2006

Journal of Biological Chemistry

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“…Following T lymphocyte activation, the death receptors of proliferating lymphocytes need to be carefully secured against apoptotic signaling via the CD95L, the expression of which is greatly elevated when the cells are activated (41)(42)(43)(44). In contrast, the T lymphocytes produced during clonal expansion need to regain their sensitivity toward death receptormediated apoptosis to be eliminated when the Ags have been cleared out (44).…”

Section: Fever-like Hyperthermia Controls T Lymphocyte Persistence Bymentioning

confidence: 99%

Fever-Like Hyperthermia Controls T Lymphocyte Persistence by Inducing Degradation of Cellular FLIPshort

Meinander

Söderström

Kaunisto

et al. 2007

The Journal of Immunology

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Fever has a major impact on immune responses by modulating survival, proliferation, and endurance of lymphocytes. Lymphocyte persistence in turn is determined by the equilibrium between death and survival-promoting factors that regulate death receptor signaling in these cells. A potential integrator of death receptor signaling is the caspase-8 inhibitor c-FLIP, the expression of which is dynamically regulated, either rapidly induced or down-regulated. In this study, we show in activated primary human T lymphocytes that hyperthermia corresponding to fever triggered down-regulation of both c-FLIP-splicing variants, c-FLIPshort (c-FLIPS) and c-FLIPlong, with consequent sensitization to apoptosis mediated by CD95 (Fas/APO-1). The c-FLIP down-regulation and subsequent sensitization was specific for hyperthermic stress. Additionally, we show that the hyperthermia-mediated down-regulation was due to increased ubiquitination and proteasomal degradation of c-FLIPS, the stability of which we have shown to be regulated by its C-terminal splicing tail. Furthermore, the induced sensitivity to CD95 ligation was independent of heat shock protein 70, as thermotolerant cells, expressing substantially elevated levels of heat shock protein 70, were not rescued from the effect of hyperthermia-mediated c-FLIP down-regulation. Our findings indicate that fever significantly influences the rate of lymphocyte elimination through depletion of c-FLIPS. Such a general regulatory mechanism for lymphocyte removal has broad ramifications for fever-mediated regulation of immune responses.

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“…In T cells, FasL expression is induced by engagement of both TCR and the costimulatory receptor CD28 (Norian et al, 2000). Full stimulation of the FasL promoter appears to be induced by cooperation of calcineurin and PKCy and involves activation of NFAT and AP-1 (Villalba et al, 1999).…”

Section: Ifn-gmentioning

confidence: 99%

Partners in transcription: NFAT and AP-1

2001

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Combinatorial regulation is a powerful mechanism that enables tight control of gene expression, via integration of multiple signaling pathways that induce di erent transcription factors required for enhanceosome assembly. The four calcium-regulated transcription factors of the NFAT family act synergistically with AP-1 (Fos/ Jun) proteins on composite DNA elements which contain adjacent NFAT and AP-1 binding sites, where they form highly stable ternary complexes to regulate the expression of diverse inducible genes. Concomitant induction of NFAT and AP-1 requires concerted activation of two di erent signaling pathways: calcium/calcineurin, which promotes NFAT dephosphorylation, nuclear translocation and activation; and protein kinase C (PKC)/Ras, which promotes the synthesis, phosphorylation and activation of members of the Fos and Jun families of transcription factors. A ®fth member of the NFAT family, NFAT5, controls the cellular response to osmotic stress, by a mechanism that requires dimer formation and is independent of calcineurin or of interaction with AP-1. Pharmacological interference with the NFAT:AP-1 interaction may be useful in selective manipulation of the immune response. Balanced activation of NFAT and AP-1 is known to be required for productive immune responses, but the role of NFAT:AP-1 interactions in other cell types and biological processes remains to be understood. Oncogene (2001) 20, 2476 ± 2489.

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The Regulation of CD95 (Fas) Ligand Expression in Primary T Cells: Induction of Promoter Activation in CD95LP-Luc Transgenic Mice

Cited by 17 publications

References 55 publications

Active Transcription of the Human FASL/CD95L/TNFSF6 Promoter Region in T Lymphocytes Involves Chromatin Remodeling

Active Transcription of the Human FASL/CD95L/TNFSF6 Promoter Region in T Lymphocytes Involves Chromatin Remodeling

Fever-Like Hyperthermia Controls T Lymphocyte Persistence by Inducing Degradation of Cellular FLIPshort

Partners in transcription: NFAT and AP-1

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