Differential inducibility of the transcriptional repressor ICER and its role in modulation of Fas ligand expression in T and NK lymphocytes

Bodor, Josef; Bodorova, Jana; Bare, Catherine V.; Hodge, Deborah L.; Young, Howard A.; Gress, Ronald E.

doi:10.1002/1521-4141(200201)32:1<203::aid-immu203>3.0.co;2-c

Cited by 22 publications

(23 citation statements)

References 33 publications

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“…We previously showed that PTH induces ICER in mouse calvariae and primary calvarial osteoblasts (19). In other systems, ICER attenuates the expression of primary response genes following cAMP induction (40)(41)(42)(43)(44)(45). Likewise, we suggest that ICER may attenuate PTH-induced gene expression in osteoblasts.…”

Section: Discussionmentioning

confidence: 66%

CREM deficiency in mice alters the response of bone to intermittent parathyroid hormone treatment

Liu

Lee

Adams

et al. 2007

Bone

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CREM belongs to the ATF/CREB family of basic leucine zipper transcription factors. We previously showed that PTH induces ICER (inducible cAMP early repressor) in osteoblasts. ICER proteins, which are transcribed from the P2 promoter of the CREM gene, act as transcriptional attenuators. The objective of this study was to determine whether the Crem gene plays a role in the response of bone to intermittent PTH. Adult Crem knockout (KO) and wild type (WT) male mice were given daily subcutaneous injections of vehicle or hPTH(1-34) (160 μg/kg) for 10 days. Bone mineral content and density (BMC and BMD, respectively) were measured in femur and tibia by dual energy X-ray absorptiometry (DEXA). Bone morphometry was analyzed by X-ray computed microtomography (microCT) and histomorphometry. Serum bone turnover markers were measured. In vitro osteoclast formation assays were performed in bone marrow cultures treated with PTH or the combination of RANKL and M-CSF. KO mice had slightly higher basal bone mass than wild type mice. PTH treatment increased tibial BMC and BMD to a greater extent in WT mice compared to KO mice. PTH increased both cortical area and trabecular bone area in WT but not in KO femurs. PTH increased the bone formation rate and percent osteoblast surface to the same extent in femurs of WT and KO mice but increased osteoclast parameters and calvarial porosity to a greater extent in KO mice. PTH increased serum osteocalcin levels to the same extent in WT and KO mice. PTHinduced osteoclast formation was 2-fold greater in bone marrow cultures from KO mice. Collectively, our data suggest that the Crem deficiency in mice alters the response of bone to intermittent PTH treatment such that osteoclastogenesis is increased. Crem gene may specify the anabolic response to intermittent PTH treatment by restraining PTH-induced osteoclastogenesis.

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Section: Discussionmentioning

confidence: 66%

CREM deficiency in mice alters the response of bone to intermittent parathyroid hormone treatment

Liu

Lee

Adams

et al. 2007

Bone

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“…This finding is further supported by the observations that T cells expressing cyclooxygenase-2 (COX-2) suppress effector Foxp3 -T cells by a PGE 2 -dependent mechanism [12]. Importantly, PGE 2 elevates intracellular levels of cAMP, which is a key physiological inducer of inducible cAMP early repressor/cAMP response element modulator (ICER/CREM) [13][14][15]. ICER/ CREM is also transiently induced by forskolin, which elevates intracellular levels of cAMP [13].…”

Section: Introductionmentioning

confidence: 72%

“…4) [48]. For example, the glucocorticoid-induced leucine zipper (GILZ) gene is an important, yet unstudied, IL-2-inhibiting transcriptional repressor showing high homology with ICER through its leucine-zipper region [15,49]. Remarkably, GILZ is coexpressed in T cells with GITR [50].…”

Section: Discussionmentioning

confidence: 99%

ICER/CREM‐mediated transcriptional attenuation of IL‐2 and its role in suppression by regulatory T cells

et al. 2007

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Here, we report that inducible cAMP early repressor/cAMP response element modulator (ICER/CREM) is induced early in CD25 + CD4 + regulatory T cell (T R ) assays mainly in activated Foxp3 -effector T cells and this induction correlates with sharp decrease in number of IL-2-expressing T cells. Importantly, RNAi targeting of ICER/CREM in responder CD25 -CD4 + T cells antagonizes T R -mediated suppression. Moreover, forced expression of Foxp3 in naive CD25 -T cells induces constitutive expression of ICER/ CREM in T cells with a regulatory phenotype. Foxp3 facilitates expression of ICER/ CREM both in Foxp3 transductants as well as CD25 -responder T cells suggesting that induction of T R function in suppression assays may utilize contact-dependent interaction. Indeed, CTLA-4 blockade or use of B7-deficient CD25 -responder T cells prevents ICER/CREM accumulation and leads to the rescue of IL-2 expression. Therefore, we propose that CTLA-4 binding to B7 ligands expressed on activated ligandbearing Foxp3 -effector T cells results in ICER/CREM-mediated transcriptional attenuation of IL-2. Collectively, these data suggest that Foxp3 expression in T R cells imposes suppression in contact-dependent fashion by induction of constitutive ICER/ CREM expression in activated CD25 + Foxp3 -T cell effectors thus preventing them from producing IL-2.

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“…Since FasL expression and activity could be "naturally" restored in highly metastatic tumors through epigenetic and genetic changes [1,4,5], we have attempted to evoke FasL-mediated apoptotic death in Faspositive melanomas. Our first attempt was to modulate the FasL transcription [45,46,59,61,[86][87][88]. A combination of COX-2 inhibitor (for suppression of PGE 2 production and PGE 2 -induced signaling cascades) and sodium arsenite as a powerful inducer of the MAPK pathways was very effective in upregulating apoptosis in COX-2-positive melanomas.…”

Section: Discussionmentioning

confidence: 99%

Dual treatment with COX-2 inhibitor and sodium arsenite leads to induction of surface Fas Ligand expression and Fas-Ligand-mediated apoptosis in human melanoma cells

Ivanov¹,

Hei²

2006

Experimental Cell Research

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Most human melanomas express Fas receptor on the cell surface, and treatment with exogenous Fas Ligand (FasL) efficiently induces apoptosis of these cells. In contrast, endogenous surface expression of FasL is suppressed in Fas-positive melanomas. We report here the use of a combination of sodium arsenite, an inhibitor of NF-κB activation, and NS398, a cyclooxygenase-2 (COX-2) inhibitor, for restoration of the surface FasL expression. We observed a large increase of Fas-mediated apoptosis in Fas-positive melanomas. This was due to induction of FasL surface expression and increased susceptibility to Fas death signaling after arsenite and NS398 treatment. Furthermore, silencing COX-2 expression by specific RNAi also effectively increased surface FasL expression following arsenite treatment. Upregulation of the surface FasL levels was based on an increase in the efficiency of translocation to the cell surface and stabilization of FasL protein on the cell surface, rather than on acceleration of the FasL gene transcription. Data obtained demonstrate that the combination of arsenite with inhibitors of COX-2 may affect the target cancer cells via induction of FasL-mediated death signaling.

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Differential inducibility of the transcriptional repressor ICER and its role in modulation of Fas ligand expression in T and NK lymphocytes

Cited by 22 publications

References 33 publications

CREM deficiency in mice alters the response of bone to intermittent parathyroid hormone treatment

CREM deficiency in mice alters the response of bone to intermittent parathyroid hormone treatment

ICER/CREM‐mediated transcriptional attenuation of IL‐2 and its role in suppression by regulatory T cells

Dual treatment with COX-2 inhibitor and sodium arsenite leads to induction of surface Fas Ligand expression and Fas-Ligand-mediated apoptosis in human melanoma cells

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