Josef Bodor - Academia.edu (original) (raw)

Papers by Josef Bodor

Research paper thumbnail of The LTR, v-src, LTR provirus generated in the mammalian genome by src mRNA reverse transcription and integration

Journal of Virology

Different types of altered proviruses of Rous sarcoma virus (RSV) have been detected in mammalian... more Different types of altered proviruses of Rous sarcoma virus (RSV) have been detected in mammalian tumor cell lines. We cloned and sequenced one of these altered proviruses with the structure LTR, v-src, LTR. The presence of an intact viral splice junction, as well as duplications of the chromosomal sequence GCGGGG flanking the two 2-base-pair-deleted LTRs, demonstrated reverse transcription and normal retroviral integration of src mRNA in mammalian cells. In addition, a 1-nucleotide deletion 2 bases upstream from the AAUAAA polyadenylation signal is suspected to be responsible for the absence of a poly(A) track in the src mRNA present in virions of rescued viruses.

Research paper thumbnail of Evidence for the Cure of HIV Infection by CCR5∆32/∆32 Stem Cell Transplantation

Journal of Human Virology & Retrovirology, 2014

Research paper thumbnail of CCR5 Targeted Cell Therapy for HIV and Prevention of Viral Escape

Viruses, 2015

Allogeneic transplantation with CCR5-delta 32 (CCR5-d32) homozygous stem cells in an HIV infected... more Allogeneic transplantation with CCR5-delta 32 (CCR5-d32) homozygous stem cells in an HIV infected individual in 2008, led to a sustained virus control and probably eradication of HIV. Since then there has been a high degree of interest to translate this approach to a wider population. There are two cellular ways to do this. The first one is to use a CCR5 negative cell source e.g., hematopoietic stem cells (HSC) to copy the initial finding. However, a recent case of a second allogeneic transplantation with CCR5-d32 homozygous stem cells suffered from viral escape of CXCR4 quasi-species. The second way is to knock down CCR5 expression by gene therapy. Currently, there are five promising techniques, three of which are presently being tested clinically. These techniques include zinc finger nucleases (ZFN), clustered regularly interspaced palindromic repeats/CRISPR-associated protein 9 nuclease (CRISPR/Cas9), transcription activator-like effectors nuclease (TALEN), short hairpin RNA (shR...

Research paper thumbnail of The Use of two Mesenchymal Stem Cell Doses as a Treatment for a Horse with Superficial Digital Flexor Tendinopathy

International Journal of Veterinary Medicine: Research & Reports, 2013

Research paper thumbnail of Complete nucleotide sequence of LTR, v- src , LTR provirus H-19

Nucleic Acids Research, 1989

Below is-the full-length DNA sequence (Z123 bp)sQ'f LTR',v-src,LTR proviris 1--19. It was generat... more Below is-the full-length DNA sequence (Z123 bp)sQ'f LTR',v-src,LTR proviris 1--19. It was generated in the hamster genome by src mRNA reverse transcription and integration (1,2,3).Duplications of the chromosomal hexanucleotide sequence GCGBGG (indicated in underlined lower-case letters in the nucleotide sequence) flanking the two 2-base-pair-deleted LTRs is characteristic for regular RSV integration.Therefore the LTR,v-src,LTR structure, originating from src mRNA instead of genomic RNA of the Prague strain C of Rous sarcoma virus (PR-RSV-C) which was rescued from rat XC cells (provirus 11 ,had produced H-19 hamster cell transformation (4,5). xcaststata g tag"aas Cuaoca s c aa a..r a at ctoogtsOot tt t ttCt

Research paper thumbnail of Molekulární klonování a sekvenování LTR, v-src, LTR provirové struktury H-19 a její využití při přípravě retrovirového vektoru /

Research paper thumbnail of Regulation of HIV-1 and IL-2 transcription by inducible CAMP early repressor (ICER)

Retrovirology

HIV-1 infection of human monocytes induces production of prostaglandin E2 (PGE2) in vitro and in ... more HIV-1 infection of human monocytes induces production of prostaglandin E2 (PGE2) in vitro and in vivo, which has capacity to make the bystander T cells unresponsive (anergic). ICER, a potent transcriptional repressor induced by PGE2 leads to transcriptional attenuation of interleukin-2 (IL-2) and an induction of T cell suppression. We propose that this HIV-1 triggered mechanism may subvert physiologically relevant suppression of IL-2 by regulatory CD4+CD25+ T (Treg) cells. Our preliminary studies suggest that the suppressive mechanism conveyed by Treg cells stems from coexpression of ICER and Foxp3, which inhibits IL-2 expression. Moreover, naïve CD4+CD25-responder T cells retrovirally transduced with Foxp3 can induce the accumulation of ICER and replace natural Treg cells. Importantly, ICER expression is induced in activated responder T cells early and correlates with a sharp decrease of IL-2 expression. Our preliminary studies indicate that ICER inhibits HIV-1 LTR expression and binds the cyclic responsive element (CRE)-like motifs termed DSE positioned downstream of transcription initiation site of HIV-1 LTR. Moreover, in monocytes PGE2 induced transcriptional attenuation of CCR5 expression tightly correlates with upregulation of ICER. We conclude that ICER is a critical component of Treg-mediated inhibitory function that affects transcriptional attenuation of IL-2 production in T cells and that HIV-1 subverts this mechanism via PGE2 and/or Tat-mediated induction of ICER.

Research paper thumbnail of Major Histocompatibility Class I Gene Transcription in Thyrocytes: A Series of Interacting Regulatory DNA Sequence Elements Mediate Thyrotropin/Cyclic Adenosine 3',5'-Monophosphate Repression

Molecular Endocrinology, Feb 1, 2000

In response to TSH, thyroid cells decrease major histocompatibility (MHC) class I expression and ... more In response to TSH, thyroid cells decrease major histocompatibility (MHC) class I expression and transcription, providing an excellent model for studying the dynamic modulation of transcription of MHC class I genes. Here we show that protein kinase A (PKA), a downstream effector of the TSH/ cAMP pathway, reproduces the effects of TSH in repressing class I transcription. PKA/cAMP-mediated repression of transcription involves multiple interacting upstream response elements in the class I promoter: an element extending from ؊127 to ؊90 bp containing a CRE-like core, and at least two elements within an upstream 30-bp segment (؊160 to ؊130 bp), which overlaps with the interferon regulatory element.

Research paper thumbnail of Regulatory T cell-mediated suppression: potential role of ICER

J Leukocyte Biol, 2006

Key Words: transcriptional repressor ⅐ inhibitory receptor ⅐ immune regulation CTLA-4 is a member... more Key Words: transcriptional repressor ⅐ inhibitory receptor ⅐ immune regulation CTLA-4 is a member of the CD28-B7 Ig superfamily of immune regulatory molecules . It shares its two ligands, B7.1

Research paper thumbnail of Therapeutic Blockade of Icer Synthesis to Prevent Icer-Mediated Inhibition of Immune Cell Activity

Research paper thumbnail of ICER/CREM-mediated transcriptional attenuation of IL-2 its role in suppression by regulatory T cells

European Journal of Immunology, 2007

Here, we report that inducible cAMP early repressor/cAMP response element modulator (ICER/CREM) i... more 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 Foxp3effector 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 CD25responder 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 CD25responder 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 Foxp3effector 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.

Research paper thumbnail of Suppression of T cell function: A potential role for transcriptional repressor ICER

Journal of Leukocyte Biology

In this article, we review the inducible cAMP early repressor (ICER) and its possible critical in... more In this article, we review the inducible cAMP early repressor (ICER) and its possible critical involvement in modulation of T cell responsiveness by its capacity to transcriptionally attenuate interleukin-2 (IL-2) gene expression. It seems clear that the failure to produce the IL-2 is an important determinant of anergy induction. It is important that the CD28-responsive element (CD28RE), a composite DNA binding element consisting of NFAT and cyclic AMP-responsive (CRE)-like motifs in position of ؊160 of IL-2 promoter has the high affinity for ICER binding as well as NFAT/ICER complex formation. Moreover, CD28RE with adjacent DNA sequences was also shown to be essential for conferring anergy in T lymphocytes. Because ICER does not possess a transactivation domain required for the recruitment of CBP/p300, the binding of ICER to CD28RE and/or composite motifs containing CRE-like DNA motifs may lead to uncoupling of CBP/p300 thus extinguishing IL-2 expression as well as expression of numerous other cytokines and chemokines. J. Leukoc. Biol. 67: 774-779; 2000.

Research paper thumbnail of Id: 227

Research paper thumbnail of BodorPNAS1996

Research paper thumbnail of Suppression of T-cell responsiveness by inducible cAMP early repressor (ICER)

Journal of leukocyte biology, 2001

Depending on the nature of the costimulation of T lymphocytes, expression of regulatory cytokines... more Depending on the nature of the costimulation of T lymphocytes, expression of regulatory cytokines and chemokines is either susceptible or resistant to cyclic AMP (cAMP)-mediated inhibition. Our data show that cAMP-mediated inhibition of endogenously expressed cytokines, which is characteristic for T helper (Th) 1- and Th 2-like phenotypes, correlates with the induction of a potent transcriptional repressor, inducible cAMP early repressor (ICER), in both subsets of T cells activated under conditions of suboptimal interleukin-2 (IL-2) expression. Importantly, Th-specific expression of certain chemokines is also susceptible to cAMP-mediated transcriptional attenuation. To determine whether ICER per se, rather than forskolin-mediated elevation of intracellular cAMP, is responsible for the observed inhibitory effect, we generated transgenic mice expressing ICER under the control of a lymphocyte-specific lck promoter. On stimulation, transgenic thymocytes overexpressing ICER exhibited red...

Research paper thumbnail of Suppression of T cell function: a potential role for transcriptional repressor ICER

Journal of leukocyte biology, 2000

In this article, we review the inducible cAMP early repressor (ICER) and its possible critical in... more In this article, we review the inducible cAMP early repressor (ICER) and its possible critical involvement in modulation of T cell responsiveness by its capacity to transcriptionally attenuate interleukin-2 (IL-2) gene expression. It seems clear that the failure to produce the IL-2 is an important determinant of anergy induction. It is important that the CD28-responsive element (CD28RE), a composite DNA binding element consisting of NFAT and cyclic AMP-responsive (CRE)-like motifs in position of -160 of IL-2 promoter has the high affinity for ICER binding as well as NFAT/ICER complex formation. Moreover, CD28RE with adjacent DNA sequences was also shown to be essential for conferring anergy in T lymphocytes. Because ICER does not possess a transactivation domain required for the recruitment of CBP/p300, the binding of ICER to CD28RE and/or composite motifs containing CRE-like DNA motifs may lead to uncoupling of CBP/p300 thus extinguishing IL-2 expression as well as expression of nu...

Research paper thumbnail of cAMP inducibility of transcriptional repressor ICER in developing and mature human T lymphocytes

Proceedings of the National Academy of Sciences, 1996

Stimulation of the cAMP-dependent signaling pathway exerts an inhibitory effect on the proliferat... more Stimulation of the cAMP-dependent signaling pathway exerts an inhibitory effect on the proliferation and effector functions of T cells. The ability of T cells to form high intracellular levels of cAMP is acquired during development in the human thymus and is retained by the majority of mature peripheral T lymphocytes. Here we show that elevated cAMP levels in T cells correlate with the expression of the potent transcriptional repressor ICER (inducible cAMP early repressor) previously described in the hypothalamicpituitary-gonadal axis. Further, in transcriptional assays in vivo, ICER inhibits calcineurin-mediated expression of the interleukin 2 promoter as well as Tax-mediated transactivation of the human T-lymphotropic virus type I (HTLV-I) promoter. Thus, the induction of ICER in T cells may play an important role in the cAMP-induced quiescence and the persistent latency of HTLV-I.

Research paper thumbnail of Major Histocompatibility Class I Gene Transcription in Thyrocytes: A Series of Interacting Regulatory DNA Sequence Elements Mediate Thyrotropin/Cyclic Adenosine 3′,5′-Monophosphate Repression

Molecular Endocrinology, 2000

In response to TSH, thyroid cells decrease major histocompatibility (MHC) class I expression and ... more In response to TSH, thyroid cells decrease major histocompatibility (MHC) class I expression and transcription, providing an excellent model for studying the dynamic modulation of transcription of MHC class I genes. Here we show that protein kinase A (PKA), a downstream effector of the TSH/ cAMP pathway, reproduces the effects of TSH in repressing class I transcription. PKA/cAMP-mediated repression of transcription involves multiple interacting upstream response elements in the class I promoter: an element extending from ؊127 to ؊90 bp containing a CRE-like core, and at least two elements within an upstream 30-bp segment (؊160 to ؊130 bp), which overlaps with the interferon regulatory element.

Research paper thumbnail of Transcriptional repression of the MHC class 1 ge4nes by thyroid stimulating hormone (TSH) involves the PKA induced repressor of transcription ICER & multiple promotor response

Journal of Neuroimmunology, 1998

Transient C5b-9 deposition on SchC of GBS patients or EAN rats does not induce eytolysis. To dete... more Transient C5b-9 deposition on SchC of GBS patients or EAN rats does not induce eytolysis. To determine if sublytie C5b-9 induces SchC mito-genesis and survival, in vitro rat SchC were stimulated with C5b-9 assembled from purified proteins (C5,6,7,8,9) in the serum-free medium, N2, or [3-neuregulin (NRG). C5b-9 increased 3H-thymidine ineorporatiun 10-fold by 24 hrs over N2 alone or N2 with heat-inactivated C5b-9. Cell cycle analysis with propidium iodide and FACS showed SehC in N2 were synchronized in GI/Go at 24 hours. C5b-9 shifted 50% into S phase similar to NP, G (100 ng/ml). C5b-9 stimulated viable SchC doubling as assesses by vital dye exclusion. Pertussis toxin and PD098,059, but not a PKA inhibitor, prevented CSb-9-mediated thymidine incorporation suggesting signal transduction was mediated via Gi proteins and ERK kinase. 40-50% SchC death following serum withdrawal and culture in N2 for 24 hrs, was prevented by NRG. Likewise, C5b-9 inhibited the number of apoptotic, TUNEL-positive SchC from 44% to 1.5%. Our data suggest that C5b-9, like NRG, is a potent trophic factor stimulating SehC mitogenesis and apoptotic rescue and may contribute to peripheral nerve repair following immune-mediated peripheral nerve demyelination.

Research paper thumbnail of Regulatory T cell-mediated suppression: potential role of ICER

Journal of Leukocyte Biology, 2006

Key Words: transcriptional repressor ⅐ inhibitory receptor ⅐ immune regulation CTLA-4 is a member... more Key Words: transcriptional repressor ⅐ inhibitory receptor ⅐ immune regulation CTLA-4 is a member of the CD28-B7 Ig superfamily of immune regulatory molecules . It shares its two ligands, B7.1

Research paper thumbnail of The LTR, v-src, LTR provirus generated in the mammalian genome by src mRNA reverse transcription and integration

Journal of Virology

Different types of altered proviruses of Rous sarcoma virus (RSV) have been detected in mammalian... more Different types of altered proviruses of Rous sarcoma virus (RSV) have been detected in mammalian tumor cell lines. We cloned and sequenced one of these altered proviruses with the structure LTR, v-src, LTR. The presence of an intact viral splice junction, as well as duplications of the chromosomal sequence GCGGGG flanking the two 2-base-pair-deleted LTRs, demonstrated reverse transcription and normal retroviral integration of src mRNA in mammalian cells. In addition, a 1-nucleotide deletion 2 bases upstream from the AAUAAA polyadenylation signal is suspected to be responsible for the absence of a poly(A) track in the src mRNA present in virions of rescued viruses.

Research paper thumbnail of Evidence for the Cure of HIV Infection by CCR5∆32/∆32 Stem Cell Transplantation

Journal of Human Virology & Retrovirology, 2014

Research paper thumbnail of CCR5 Targeted Cell Therapy for HIV and Prevention of Viral Escape

Viruses, 2015

Allogeneic transplantation with CCR5-delta 32 (CCR5-d32) homozygous stem cells in an HIV infected... more Allogeneic transplantation with CCR5-delta 32 (CCR5-d32) homozygous stem cells in an HIV infected individual in 2008, led to a sustained virus control and probably eradication of HIV. Since then there has been a high degree of interest to translate this approach to a wider population. There are two cellular ways to do this. The first one is to use a CCR5 negative cell source e.g., hematopoietic stem cells (HSC) to copy the initial finding. However, a recent case of a second allogeneic transplantation with CCR5-d32 homozygous stem cells suffered from viral escape of CXCR4 quasi-species. The second way is to knock down CCR5 expression by gene therapy. Currently, there are five promising techniques, three of which are presently being tested clinically. These techniques include zinc finger nucleases (ZFN), clustered regularly interspaced palindromic repeats/CRISPR-associated protein 9 nuclease (CRISPR/Cas9), transcription activator-like effectors nuclease (TALEN), short hairpin RNA (shR...

Research paper thumbnail of The Use of two Mesenchymal Stem Cell Doses as a Treatment for a Horse with Superficial Digital Flexor Tendinopathy

International Journal of Veterinary Medicine: Research & Reports, 2013

Research paper thumbnail of Complete nucleotide sequence of LTR, v- src , LTR provirus H-19

Nucleic Acids Research, 1989

Below is-the full-length DNA sequence (Z123 bp)sQ'f LTR',v-src,LTR proviris 1--19. It was generat... more Below is-the full-length DNA sequence (Z123 bp)sQ'f LTR',v-src,LTR proviris 1--19. It was generated in the hamster genome by src mRNA reverse transcription and integration (1,2,3).Duplications of the chromosomal hexanucleotide sequence GCGBGG (indicated in underlined lower-case letters in the nucleotide sequence) flanking the two 2-base-pair-deleted LTRs is characteristic for regular RSV integration.Therefore the LTR,v-src,LTR structure, originating from src mRNA instead of genomic RNA of the Prague strain C of Rous sarcoma virus (PR-RSV-C) which was rescued from rat XC cells (provirus 11 ,had produced H-19 hamster cell transformation (4,5). xcaststata g tag"aas Cuaoca s c aa a..r a at ctoogtsOot tt t ttCt

Research paper thumbnail of Molekulární klonování a sekvenování LTR, v-src, LTR provirové struktury H-19 a její využití při přípravě retrovirového vektoru /

Research paper thumbnail of Regulation of HIV-1 and IL-2 transcription by inducible CAMP early repressor (ICER)

Retrovirology

HIV-1 infection of human monocytes induces production of prostaglandin E2 (PGE2) in vitro and in ... more HIV-1 infection of human monocytes induces production of prostaglandin E2 (PGE2) in vitro and in vivo, which has capacity to make the bystander T cells unresponsive (anergic). ICER, a potent transcriptional repressor induced by PGE2 leads to transcriptional attenuation of interleukin-2 (IL-2) and an induction of T cell suppression. We propose that this HIV-1 triggered mechanism may subvert physiologically relevant suppression of IL-2 by regulatory CD4+CD25+ T (Treg) cells. Our preliminary studies suggest that the suppressive mechanism conveyed by Treg cells stems from coexpression of ICER and Foxp3, which inhibits IL-2 expression. Moreover, naïve CD4+CD25-responder T cells retrovirally transduced with Foxp3 can induce the accumulation of ICER and replace natural Treg cells. Importantly, ICER expression is induced in activated responder T cells early and correlates with a sharp decrease of IL-2 expression. Our preliminary studies indicate that ICER inhibits HIV-1 LTR expression and binds the cyclic responsive element (CRE)-like motifs termed DSE positioned downstream of transcription initiation site of HIV-1 LTR. Moreover, in monocytes PGE2 induced transcriptional attenuation of CCR5 expression tightly correlates with upregulation of ICER. We conclude that ICER is a critical component of Treg-mediated inhibitory function that affects transcriptional attenuation of IL-2 production in T cells and that HIV-1 subverts this mechanism via PGE2 and/or Tat-mediated induction of ICER.

Research paper thumbnail of Major Histocompatibility Class I Gene Transcription in Thyrocytes: A Series of Interacting Regulatory DNA Sequence Elements Mediate Thyrotropin/Cyclic Adenosine 3',5'-Monophosphate Repression

Molecular Endocrinology, Feb 1, 2000

In response to TSH, thyroid cells decrease major histocompatibility (MHC) class I expression and ... more In response to TSH, thyroid cells decrease major histocompatibility (MHC) class I expression and transcription, providing an excellent model for studying the dynamic modulation of transcription of MHC class I genes. Here we show that protein kinase A (PKA), a downstream effector of the TSH/ cAMP pathway, reproduces the effects of TSH in repressing class I transcription. PKA/cAMP-mediated repression of transcription involves multiple interacting upstream response elements in the class I promoter: an element extending from ؊127 to ؊90 bp containing a CRE-like core, and at least two elements within an upstream 30-bp segment (؊160 to ؊130 bp), which overlaps with the interferon regulatory element.

Research paper thumbnail of Regulatory T cell-mediated suppression: potential role of ICER

J Leukocyte Biol, 2006

Key Words: transcriptional repressor ⅐ inhibitory receptor ⅐ immune regulation CTLA-4 is a member... more Key Words: transcriptional repressor ⅐ inhibitory receptor ⅐ immune regulation CTLA-4 is a member of the CD28-B7 Ig superfamily of immune regulatory molecules . It shares its two ligands, B7.1

Research paper thumbnail of Therapeutic Blockade of Icer Synthesis to Prevent Icer-Mediated Inhibition of Immune Cell Activity

Research paper thumbnail of ICER/CREM-mediated transcriptional attenuation of IL-2 its role in suppression by regulatory T cells

European Journal of Immunology, 2007

Here, we report that inducible cAMP early repressor/cAMP response element modulator (ICER/CREM) i... more 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 Foxp3effector 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 CD25responder 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 CD25responder 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 Foxp3effector 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.

Research paper thumbnail of Suppression of T cell function: A potential role for transcriptional repressor ICER

Journal of Leukocyte Biology

In this article, we review the inducible cAMP early repressor (ICER) and its possible critical in... more In this article, we review the inducible cAMP early repressor (ICER) and its possible critical involvement in modulation of T cell responsiveness by its capacity to transcriptionally attenuate interleukin-2 (IL-2) gene expression. It seems clear that the failure to produce the IL-2 is an important determinant of anergy induction. It is important that the CD28-responsive element (CD28RE), a composite DNA binding element consisting of NFAT and cyclic AMP-responsive (CRE)-like motifs in position of ؊160 of IL-2 promoter has the high affinity for ICER binding as well as NFAT/ICER complex formation. Moreover, CD28RE with adjacent DNA sequences was also shown to be essential for conferring anergy in T lymphocytes. Because ICER does not possess a transactivation domain required for the recruitment of CBP/p300, the binding of ICER to CD28RE and/or composite motifs containing CRE-like DNA motifs may lead to uncoupling of CBP/p300 thus extinguishing IL-2 expression as well as expression of numerous other cytokines and chemokines. J. Leukoc. Biol. 67: 774-779; 2000.

Research paper thumbnail of Id: 227

Research paper thumbnail of BodorPNAS1996

Research paper thumbnail of Suppression of T-cell responsiveness by inducible cAMP early repressor (ICER)

Journal of leukocyte biology, 2001

Depending on the nature of the costimulation of T lymphocytes, expression of regulatory cytokines... more Depending on the nature of the costimulation of T lymphocytes, expression of regulatory cytokines and chemokines is either susceptible or resistant to cyclic AMP (cAMP)-mediated inhibition. Our data show that cAMP-mediated inhibition of endogenously expressed cytokines, which is characteristic for T helper (Th) 1- and Th 2-like phenotypes, correlates with the induction of a potent transcriptional repressor, inducible cAMP early repressor (ICER), in both subsets of T cells activated under conditions of suboptimal interleukin-2 (IL-2) expression. Importantly, Th-specific expression of certain chemokines is also susceptible to cAMP-mediated transcriptional attenuation. To determine whether ICER per se, rather than forskolin-mediated elevation of intracellular cAMP, is responsible for the observed inhibitory effect, we generated transgenic mice expressing ICER under the control of a lymphocyte-specific lck promoter. On stimulation, transgenic thymocytes overexpressing ICER exhibited red...

Research paper thumbnail of Suppression of T cell function: a potential role for transcriptional repressor ICER

Journal of leukocyte biology, 2000

In this article, we review the inducible cAMP early repressor (ICER) and its possible critical in... more In this article, we review the inducible cAMP early repressor (ICER) and its possible critical involvement in modulation of T cell responsiveness by its capacity to transcriptionally attenuate interleukin-2 (IL-2) gene expression. It seems clear that the failure to produce the IL-2 is an important determinant of anergy induction. It is important that the CD28-responsive element (CD28RE), a composite DNA binding element consisting of NFAT and cyclic AMP-responsive (CRE)-like motifs in position of -160 of IL-2 promoter has the high affinity for ICER binding as well as NFAT/ICER complex formation. Moreover, CD28RE with adjacent DNA sequences was also shown to be essential for conferring anergy in T lymphocytes. Because ICER does not possess a transactivation domain required for the recruitment of CBP/p300, the binding of ICER to CD28RE and/or composite motifs containing CRE-like DNA motifs may lead to uncoupling of CBP/p300 thus extinguishing IL-2 expression as well as expression of nu...

Research paper thumbnail of cAMP inducibility of transcriptional repressor ICER in developing and mature human T lymphocytes

Proceedings of the National Academy of Sciences, 1996

Stimulation of the cAMP-dependent signaling pathway exerts an inhibitory effect on the proliferat... more Stimulation of the cAMP-dependent signaling pathway exerts an inhibitory effect on the proliferation and effector functions of T cells. The ability of T cells to form high intracellular levels of cAMP is acquired during development in the human thymus and is retained by the majority of mature peripheral T lymphocytes. Here we show that elevated cAMP levels in T cells correlate with the expression of the potent transcriptional repressor ICER (inducible cAMP early repressor) previously described in the hypothalamicpituitary-gonadal axis. Further, in transcriptional assays in vivo, ICER inhibits calcineurin-mediated expression of the interleukin 2 promoter as well as Tax-mediated transactivation of the human T-lymphotropic virus type I (HTLV-I) promoter. Thus, the induction of ICER in T cells may play an important role in the cAMP-induced quiescence and the persistent latency of HTLV-I.

Research paper thumbnail of Major Histocompatibility Class I Gene Transcription in Thyrocytes: A Series of Interacting Regulatory DNA Sequence Elements Mediate Thyrotropin/Cyclic Adenosine 3′,5′-Monophosphate Repression

Molecular Endocrinology, 2000

In response to TSH, thyroid cells decrease major histocompatibility (MHC) class I expression and ... more In response to TSH, thyroid cells decrease major histocompatibility (MHC) class I expression and transcription, providing an excellent model for studying the dynamic modulation of transcription of MHC class I genes. Here we show that protein kinase A (PKA), a downstream effector of the TSH/ cAMP pathway, reproduces the effects of TSH in repressing class I transcription. PKA/cAMP-mediated repression of transcription involves multiple interacting upstream response elements in the class I promoter: an element extending from ؊127 to ؊90 bp containing a CRE-like core, and at least two elements within an upstream 30-bp segment (؊160 to ؊130 bp), which overlaps with the interferon regulatory element.

Research paper thumbnail of Transcriptional repression of the MHC class 1 ge4nes by thyroid stimulating hormone (TSH) involves the PKA induced repressor of transcription ICER & multiple promotor response

Journal of Neuroimmunology, 1998

Transient C5b-9 deposition on SchC of GBS patients or EAN rats does not induce eytolysis. To dete... more Transient C5b-9 deposition on SchC of GBS patients or EAN rats does not induce eytolysis. To determine if sublytie C5b-9 induces SchC mito-genesis and survival, in vitro rat SchC were stimulated with C5b-9 assembled from purified proteins (C5,6,7,8,9) in the serum-free medium, N2, or [3-neuregulin (NRG). C5b-9 increased 3H-thymidine ineorporatiun 10-fold by 24 hrs over N2 alone or N2 with heat-inactivated C5b-9. Cell cycle analysis with propidium iodide and FACS showed SehC in N2 were synchronized in GI/Go at 24 hours. C5b-9 shifted 50% into S phase similar to NP, G (100 ng/ml). C5b-9 stimulated viable SchC doubling as assesses by vital dye exclusion. Pertussis toxin and PD098,059, but not a PKA inhibitor, prevented CSb-9-mediated thymidine incorporation suggesting signal transduction was mediated via Gi proteins and ERK kinase. 40-50% SchC death following serum withdrawal and culture in N2 for 24 hrs, was prevented by NRG. Likewise, C5b-9 inhibited the number of apoptotic, TUNEL-positive SchC from 44% to 1.5%. Our data suggest that C5b-9, like NRG, is a potent trophic factor stimulating SehC mitogenesis and apoptotic rescue and may contribute to peripheral nerve repair following immune-mediated peripheral nerve demyelination.

Research paper thumbnail of Regulatory T cell-mediated suppression: potential role of ICER

Journal of Leukocyte Biology, 2006

Key Words: transcriptional repressor ⅐ inhibitory receptor ⅐ immune regulation CTLA-4 is a member... more Key Words: transcriptional repressor ⅐ inhibitory receptor ⅐ immune regulation CTLA-4 is a member of the CD28-B7 Ig superfamily of immune regulatory molecules . It shares its two ligands, B7.1