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Papers by marjaneh razmara

Research paper thumbnail of FN14/TRAIL Fusion Proteins

Research paper thumbnail of Fn 14/TRAIL Fusion Proteins

Research paper thumbnail of Fn14/TRAIL fusion proteins

Research paper thumbnail of Mitochondrial Biogenesis

influence of the p53 tumor suppressor on

Research paper thumbnail of Activating Adaptor for Caspase-1 The PYRIN-CARD Protein ASC Is an ACCELERATED PUBLICATION

Research paper thumbnail of Protéines de fusion fn14/trail

L'invention concerne des proteines de fusion qui agissent sur les axes de signalisation TWEAK... more L'invention concerne des proteines de fusion qui agissent sur les axes de signalisation TWEAK et TRAIL. Les proteines sont utiles pour le traitement ou l'amelioration de maladies auto-immunes, notamment de la sclerose en plaques, ainsi que d'autres maladies telles que les maladies allo-immunes et le cancer.

Research paper thumbnail of CTLA-4Ig converts naive CD4 1 CD25 2 T cells into CD4 1 CD25 1 regulatory T cells

CTLA-4Ig was originally designed as an immunosuppressive agent capable of interfering with the co... more CTLA-4Ig was originally designed as an immunosuppressive agent capable of interfering with the co-stimulation of T cells. In the present study, we demonstrate that CTLA-4Ig, in combination with TCR ligation, has the additional capacity to convert naive CD4 1 CD25 2 T cells into Foxp3 1 regulatory T (Treg) cells, as well as to expand their numbers. The CD4 1 CD25 1 Foxp3 1 Treg generated by CTLA-4Ig treatment in vitro potently suppress effector T cells. Extending this in vivo, we show that systemic administration of CTLA-4Ig increases the percentage of CD4 1 CD25 hi Foxp3 1 cells within mixed lymphocyte reaction-induced murine lymph nodes. Significantly, the in vitro conversion of naive CD4 1 CD25 2 T cells into Treg cells is antigen-presenting cell (APC) dependent. This finding, together with the further observation that this conversion can also be driven in vitro by an antibody that engages B7-2 ligand, suggests that CTLA-4Ig-driven Treg induction may be predicated upon active CTLA...

Research paper thumbnail of Ig converts naive CD 4 1 CD 25 2 T cells into CD 4 1 CD 25 1 regulatory T cells

CTLA-4 Ig was originally designed as an immunosuppressive agent capable of interfering with the c... more CTLA-4 Ig was originally designed as an immunosuppressive agent capable of interfering with the co-stimulation of T cells. In the present study, we demonstrate that CTLA-4 Ig, in combination with TCR ligation, has the additional capacity to convert naive CD4CD25 T cells into Foxp3 regulatory T (Treg) cells, as well as to expand their numbers. The CD4CD25Foxp3 Treg generated by CTLA-4 Ig treatment in vitro potently suppress effector T cells. Extending this in vivo, we show that systemic administration of CTLA-4 Ig increases the percentage of CD4CD25Foxp3 cells within mixed lymphocyte reaction-induced murine lymph nodes. Significantly, the in vitro conversion of naive CD4CD25 T cells into Treg cells is antigen-presenting cell (APC) dependent. This finding, together with the further observation that this conversion can also be driven in vitro by an antibody that engages B7-2 ligand, suggests that CTLA-4 Ig-driven Treg induction may be predicated upon active CTLA-4 Ig to B7-2 signaling ...

Research paper thumbnail of Immunopathology and Infectious Diseases Fn 14-TRAIL , a Chimeric Intercellular Signal Exchanger , Attenuates Experimental Autoimmune Encephalomyelitis

Hallmarks of the pathogenesis of autoimmune encephalomyelitis include perivascular infiltration o... more Hallmarks of the pathogenesis of autoimmune encephalomyelitis include perivascular infiltration of inflammatory cells into the central nervous system, multifocal demyelination in the brain and spinal cord, and focal neuronal degeneration. Optimal treatment of this complex disease will ultimately call for agents that target the spectrum of underlying pathogenic processes. In the present study, Fn14-TRAIL is introduced as a unique immunotherapeutic fusion protein that is designed to exchange and redirect intercellular signals within inflammatory cell networks, and, in so doing, to impact multiple pathogenic events and yield a net anti-inflammatory effect. In this soluble protein product, a Fn14 receptor component (capable of blocking the pro-inflammatory TWEAK ligand) is fused to a TRAIL ligand (capable of inhibiting activated, pathogenic T cells). Sustained Fn14-TRAIL expression was obtained in vivo using a transposon-based eukaryotic expression vector. Fn14-TRAIL expression effectiv...

Research paper thumbnail of Apaf-1 Caspase-1-activating Protein Related to Identification of Ipaf, a Human TRANSDUCTION: MECHANISMS OF SIGNAL

doi: 10.1074/jbc.C100250200 originally published online June 4, 2001J. Biol. Chem.€2001, 276:2830... more doi: 10.1074/jbc.C100250200 originally published online June 4, 2001J. Biol. Chem.€2001, 276:28309-28313.€ Access the most updated version of this article at doi: 10.1074/jbc.C100250200 € Find articles, minireviews, Reflections and Classics on similar topics on the JBC Affinity Sites.Alerts: €€ •€ When a correction for this article is posted •€ When this article is cited Click here to choose from all of JBC's e-mail alerts€ http://www.jbc.org/content/276/30/28309.full.html#ref-list-1 This article cites 0 references, 0 of which can be accessed free at

Research paper thumbnail of Transcription of the JC virus archetype late genome: importance of the kappa B and the 23-base-pair motifs in late promoter activity in glial cells

Journal of Virology, 1996

The transcription control region of the archetype strain of the human polyomavirus JC virus (JCV(... more The transcription control region of the archetype strain of the human polyomavirus JC virus (JCV(Cy)), unlike its neurotropic counterpart (JCV(Mad-1)), contains only one copy of the 98-bp enhancer/promoter repeat with the 23-bp and the 66-bp insertion blocks. Early studies by us and others have indicated that the structural organization of JCV(Mad-1) is critical for glial cell-specific transcription of the viral genome. In addition, the kappa B regulatory motif found in the JCV(Mad-1) genome, which also exists in JCV(Cy), confers inducibility to the JCV(Mad-1) early and late promoters in response to extracellular stimuli. In this study, we have investigated the regulatory role of the 23- and the 66-bp blocks and their functional relationship to the kappa B motif in stimulating transcription of the Cy early and late promoters in glial cells. We demonstrate that mutations in the kappa B motif reduce the basal activity of the Cy early promoter and decrease the levels of its induction b...

Research paper thumbnail of FN14/TRAIL Fusion Proteins

Research paper thumbnail of Ice and card containing proteins: Dancing between life and death

Research paper thumbnail of Direct influence of the p53 tumor suppressor on mitochondrial biogenesis and function

The FASEB Journal, 2001

Mitochondrial localization of p53 has been observed in several cell systems, but an understanding... more Mitochondrial localization of p53 has been observed in several cell systems, but an understanding of its organelle-based physiological activity remains incomplete. The purpose of the present study was to investigate the mitochondrial DNA genomic response to dominant-negative p53 mutant miniprotein (p53DD) fused to a mitochondrial import signal. Constructs were generated to express mitochondrial targeted enhanced green fluorescent protein (mEGFP) or dominant-negative mutant p53 miniprotein (m53DD) by in-frame fusion to the signal peptide sequence of murine Cox8l. Control cytosolic vectors (cEGFP, c53DD) had the signal sequence placed in antisense orientation. NIH 3T3 cells were transiently transfected with these vectors in various combinations. Mitochondrial 16S ribosomal RNA (16S rRNA) expression and fluorochrome staining with Mitotracker Red CMXRos (⌬⌿m) were decreased in cells expressing m53DD. Both alterations were specific for mitochondrial import competence (e.g., m53DD vs. c53DD) as well as the passenger protein (e.g., m53DD vs. mEGFP). The normal functional state of mitochondria was restored with PK11195, a specific ligand of the mitochondrial peripheral-type benzodiazepine receptor. Negative dominance of m53DD on 16S rRNA expression and CMXRos staining, and rescue of these parameters with PK11195, imply a direct positive effect of p53 on mitochondrial biogenesis and function.-Donahue, R.

Research paper thumbnail of CARD-8 Protein, a New CARD Family Member That Regulates Caspase-1 Activation and Apoptosis

Journal of Biological Chemistry, 2002

Caspase-associated recruitment domains (CARD) are protein-protein interaction modules found exten... more Caspase-associated recruitment domains (CARD) are protein-protein interaction modules found extensively in proteins that play important roles in apoptosis, NFB activation, and cytokine regulation. In this study we identified a novel human protein, CARD-8, which contains a C-terminal CARD domain with high similarity to the CARD domain of caspase-1/ICE. We demonstrate that CARD-8 interacts physically with caspase-1 and negatively regulates caspase-1-dependent IL-1␤ generation in the THP-1 monocytic cell line. CARD-8 binds also to ICEBERG and pseudo-ICE, two other recently identified proteins, which bind to the CARD domain of caspase-1 and negatively regulate its activity. Reverse transcriptase-PCR analysis revealed that CARD-8 is expressed mainly in monocytes, placenta, lymph nodes, and spleen. This pattern of expression is consistent with caspase-1 expression in the same cells and tissues. CARD-8 was also found to negatively regulate NF-B activation by TNF-␣ stimulation and by ectopically expressed RICK, suggesting that this protein may control cell survival. Consistent with these results, stable expression of CARD-8 in U937 or THP-1 cells sensitizes the cells to differentiation-induced apoptosis. Overexpression of CARD-8 can also induce apoptosis in transfected cells. The results suggest that CARD-8 represents a new signaling molecule involved in the regulation of caspase-1 and NF-B activation.

Research paper thumbnail of Identification of Ipaf, a Human Caspase-1-activating Protein Related to Apaf-1

Journal of Biological Chemistry, 2001

Research paper thumbnail of The PYRIN-CARD Protein ASC Is an Activating Adaptor for Caspase-1

Journal of Biological Chemistry, 2002

The PYRIN and CARD domains are members of the six-helix bundle death domain-fold superfamily that... more The PYRIN and CARD domains are members of the six-helix bundle death domain-fold superfamily that mediates assembly of large signaling complexes in the apoptotic and inflammatory signaling pathways. Here we show that the PYRIN-CARD protein ASC functions as a caspase-1-activating adaptor. ASC interacted specifically with procaspase-1 via CARD-CARD interactions and induced its oligomerization. Consistent with these results ectopic expression of full-length ASC, but not its isolated CARD or PYRIN domain, with procaspase-1 induced activation of procaspase-1 and processing of prointerleukin-1␤ in transfected cells. Substitution of the PYRIN domain of ASC with an inducible FKBP12 oligomerization domain produced a molecule that can induce caspase-1 activation in response to stimulation with the oligomerization drug AP20187, suggesting that the PYRIN domain functions as an oligomerization domain, whereas the CARD domain functions as the effector domain in the caspase-1 activation pathway. Furthermore stable expression of an isolated CARD of ASC in THP-1 cells diminished interleukin-1␤ generation in response to pro-inflammatory cytokines. These results indicate that ASC is involved in the caspase-1 signaling pathway by mediating the assembly of a caspase-1-inflammasome signaling complex in response to pro-inflammatory cytokine stimulation.

Research paper thumbnail of CTLA-4{middle dot}Ig converts naive CD4+CD25- T cells into CD4+CD25+ regulatory T cells

International Immunology, 2008

CTLA-4ÁIg was originally designed as an immunosuppressive agent capable of interfering with the c... more CTLA-4ÁIg was originally designed as an immunosuppressive agent capable of interfering with the co-stimulation of T cells. In the present study, we demonstrate that CTLA-4ÁIg, in combination with TCR ligation, has the additional capacity to convert naive CD4 1 CD25 2 T cells into Foxp3 1 regulatory T (T reg) cells, as well as to expand their numbers. The CD4 1 CD25 1 Foxp3 1 T reg generated by CTLA-4ÁIg treatment in vitro potently suppress effector T cells. Extending this in vivo, we show that systemic administration of CTLA-4ÁIg increases the percentage of CD4 1 CD25 hi Foxp3 1 cells within mixed lymphocyte reaction-induced murine lymph nodes. Significantly, the in vitro conversion of naive CD4 1 CD25 2 T cells into T reg cells is antigen-presenting cell (APC) dependent. This finding, together with the further observation that this conversion can also be driven in vitro by an antibody that engages B7-2 ligand, suggests that CTLA-4ÁIg-driven T reg induction may be predicated upon active CTLA-4ÁIg to B7-2 signaling within APC, which elicits from them T reg-inducing potential. These findings extend CTLA-4ÁIg's functional repertoire, and at the same time, reinforce the concept that T cell anergy and active suppression are not entirely distinct processes and may be linked by some common molecular triggers.

Research paper thumbnail of Regulation of IL-1β generation by Pseudo-ICE and ICEBERG, two dominant negative caspase recruitment domain proteins

Cell Death & Differentiation, 2001

We report here the identification and functional characterization of two new human caspase recrui... more We report here the identification and functional characterization of two new human caspase recruitment domain (CARD) molecules, termed Pseudo-interleukin-1b converting enzyme (ICE) and ICEBERG. Both proteins share a high degree of homology, reaching 92% and 53% identity, respectively, to the prodomain of caspase-1/ICE. Interestingly, both Pseudo-ICE and ICEBERG are mapped to chromosome 11q22 that bears caspases-1,-4-and-5 genes, all involved in cytokine production rather than in apoptosis. We demonstrate that Pseudo-ICE and ICEBERG interact physically with caspase-1 and block, in a monocytic cell line, the interferon-g and lipopolysaccharide-induced secretion of interleukin-1b which is a well-known consequence of caspase-1 activation. Moreover, Pseudo-ICE, but not ICEBERG, interacts with the CARD-containing kinase RICK/RIP2/CARDIAK and activates NF-kB. Our data suggest that Pseudo-ICE and ICEBERG are intracellular regulators of caspase-1 activation and could play a role in the regulation of IL-1b secretion and NF-kB activation during the pro-inflammatory cytokine response. Cell Death and Differentiation (2001) 8, 649 ± 657.

Research paper thumbnail of Altered expression of mitochondrial 16S ribosomal RNA in p53-deficient mouse embryos revealed by differential display

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 1998

Inactivation of the tumor suppressor p53 is associated with neural tube defects and altered terat... more Inactivation of the tumor suppressor p53 is associated with neural tube defects and altered teratogenicity in early embryos. To gain insight into the function of p53 during early embryogenesis, RNA profiles of wild-type p53(+/+) and p53(3/3) null mutant mouse embryos were compared at the head-fold stage (day 8 post coitum) using HPLC-based mRNA differential display. The results of this screen revealed a deficiency of mitochondrial 16S ribosomal RNA in p53(3/3) embryos. RT-PCR showed abnormalities in 16S rRNA levels relative to some representative nuclear (COIV, L-actin) and mitochondrial (COIII) transcripts in p53(3/3) embryos, and that 16S rRNA expression increased with development of p53(+/+) embryos during neurulation. Embryos that lack p53 also displayed weakened cytochrome c oxidase staining and reduced ATP content. During neurulation, the mouse embryo switches from an anaerobic (glycolytic) to an aerobic (oxidative) metabolism. The preliminary results of the present study suggest that p53 may be involved, directly or indirectly, in this transition.

Research paper thumbnail of FN14/TRAIL Fusion Proteins

Research paper thumbnail of Fn 14/TRAIL Fusion Proteins

Research paper thumbnail of Fn14/TRAIL fusion proteins

Research paper thumbnail of Mitochondrial Biogenesis

influence of the p53 tumor suppressor on

Research paper thumbnail of Activating Adaptor for Caspase-1 The PYRIN-CARD Protein ASC Is an ACCELERATED PUBLICATION

Research paper thumbnail of Protéines de fusion fn14/trail

L'invention concerne des proteines de fusion qui agissent sur les axes de signalisation TWEAK... more L'invention concerne des proteines de fusion qui agissent sur les axes de signalisation TWEAK et TRAIL. Les proteines sont utiles pour le traitement ou l'amelioration de maladies auto-immunes, notamment de la sclerose en plaques, ainsi que d'autres maladies telles que les maladies allo-immunes et le cancer.

Research paper thumbnail of CTLA-4Ig converts naive CD4 1 CD25 2 T cells into CD4 1 CD25 1 regulatory T cells

CTLA-4Ig was originally designed as an immunosuppressive agent capable of interfering with the co... more CTLA-4Ig was originally designed as an immunosuppressive agent capable of interfering with the co-stimulation of T cells. In the present study, we demonstrate that CTLA-4Ig, in combination with TCR ligation, has the additional capacity to convert naive CD4 1 CD25 2 T cells into Foxp3 1 regulatory T (Treg) cells, as well as to expand their numbers. The CD4 1 CD25 1 Foxp3 1 Treg generated by CTLA-4Ig treatment in vitro potently suppress effector T cells. Extending this in vivo, we show that systemic administration of CTLA-4Ig increases the percentage of CD4 1 CD25 hi Foxp3 1 cells within mixed lymphocyte reaction-induced murine lymph nodes. Significantly, the in vitro conversion of naive CD4 1 CD25 2 T cells into Treg cells is antigen-presenting cell (APC) dependent. This finding, together with the further observation that this conversion can also be driven in vitro by an antibody that engages B7-2 ligand, suggests that CTLA-4Ig-driven Treg induction may be predicated upon active CTLA...

Research paper thumbnail of Ig converts naive CD 4 1 CD 25 2 T cells into CD 4 1 CD 25 1 regulatory T cells

CTLA-4 Ig was originally designed as an immunosuppressive agent capable of interfering with the c... more CTLA-4 Ig was originally designed as an immunosuppressive agent capable of interfering with the co-stimulation of T cells. In the present study, we demonstrate that CTLA-4 Ig, in combination with TCR ligation, has the additional capacity to convert naive CD4CD25 T cells into Foxp3 regulatory T (Treg) cells, as well as to expand their numbers. The CD4CD25Foxp3 Treg generated by CTLA-4 Ig treatment in vitro potently suppress effector T cells. Extending this in vivo, we show that systemic administration of CTLA-4 Ig increases the percentage of CD4CD25Foxp3 cells within mixed lymphocyte reaction-induced murine lymph nodes. Significantly, the in vitro conversion of naive CD4CD25 T cells into Treg cells is antigen-presenting cell (APC) dependent. This finding, together with the further observation that this conversion can also be driven in vitro by an antibody that engages B7-2 ligand, suggests that CTLA-4 Ig-driven Treg induction may be predicated upon active CTLA-4 Ig to B7-2 signaling ...

Research paper thumbnail of Immunopathology and Infectious Diseases Fn 14-TRAIL , a Chimeric Intercellular Signal Exchanger , Attenuates Experimental Autoimmune Encephalomyelitis

Hallmarks of the pathogenesis of autoimmune encephalomyelitis include perivascular infiltration o... more Hallmarks of the pathogenesis of autoimmune encephalomyelitis include perivascular infiltration of inflammatory cells into the central nervous system, multifocal demyelination in the brain and spinal cord, and focal neuronal degeneration. Optimal treatment of this complex disease will ultimately call for agents that target the spectrum of underlying pathogenic processes. In the present study, Fn14-TRAIL is introduced as a unique immunotherapeutic fusion protein that is designed to exchange and redirect intercellular signals within inflammatory cell networks, and, in so doing, to impact multiple pathogenic events and yield a net anti-inflammatory effect. In this soluble protein product, a Fn14 receptor component (capable of blocking the pro-inflammatory TWEAK ligand) is fused to a TRAIL ligand (capable of inhibiting activated, pathogenic T cells). Sustained Fn14-TRAIL expression was obtained in vivo using a transposon-based eukaryotic expression vector. Fn14-TRAIL expression effectiv...

Research paper thumbnail of Apaf-1 Caspase-1-activating Protein Related to Identification of Ipaf, a Human TRANSDUCTION: MECHANISMS OF SIGNAL

doi: 10.1074/jbc.C100250200 originally published online June 4, 2001J. Biol. Chem.€2001, 276:2830... more doi: 10.1074/jbc.C100250200 originally published online June 4, 2001J. Biol. Chem.€2001, 276:28309-28313.€ Access the most updated version of this article at doi: 10.1074/jbc.C100250200 € Find articles, minireviews, Reflections and Classics on similar topics on the JBC Affinity Sites.Alerts: €€ •€ When a correction for this article is posted •€ When this article is cited Click here to choose from all of JBC's e-mail alerts€ http://www.jbc.org/content/276/30/28309.full.html#ref-list-1 This article cites 0 references, 0 of which can be accessed free at

Research paper thumbnail of Transcription of the JC virus archetype late genome: importance of the kappa B and the 23-base-pair motifs in late promoter activity in glial cells

Journal of Virology, 1996

The transcription control region of the archetype strain of the human polyomavirus JC virus (JCV(... more The transcription control region of the archetype strain of the human polyomavirus JC virus (JCV(Cy)), unlike its neurotropic counterpart (JCV(Mad-1)), contains only one copy of the 98-bp enhancer/promoter repeat with the 23-bp and the 66-bp insertion blocks. Early studies by us and others have indicated that the structural organization of JCV(Mad-1) is critical for glial cell-specific transcription of the viral genome. In addition, the kappa B regulatory motif found in the JCV(Mad-1) genome, which also exists in JCV(Cy), confers inducibility to the JCV(Mad-1) early and late promoters in response to extracellular stimuli. In this study, we have investigated the regulatory role of the 23- and the 66-bp blocks and their functional relationship to the kappa B motif in stimulating transcription of the Cy early and late promoters in glial cells. We demonstrate that mutations in the kappa B motif reduce the basal activity of the Cy early promoter and decrease the levels of its induction b...

Research paper thumbnail of FN14/TRAIL Fusion Proteins

Research paper thumbnail of Ice and card containing proteins: Dancing between life and death

Research paper thumbnail of Direct influence of the p53 tumor suppressor on mitochondrial biogenesis and function

The FASEB Journal, 2001

Mitochondrial localization of p53 has been observed in several cell systems, but an understanding... more Mitochondrial localization of p53 has been observed in several cell systems, but an understanding of its organelle-based physiological activity remains incomplete. The purpose of the present study was to investigate the mitochondrial DNA genomic response to dominant-negative p53 mutant miniprotein (p53DD) fused to a mitochondrial import signal. Constructs were generated to express mitochondrial targeted enhanced green fluorescent protein (mEGFP) or dominant-negative mutant p53 miniprotein (m53DD) by in-frame fusion to the signal peptide sequence of murine Cox8l. Control cytosolic vectors (cEGFP, c53DD) had the signal sequence placed in antisense orientation. NIH 3T3 cells were transiently transfected with these vectors in various combinations. Mitochondrial 16S ribosomal RNA (16S rRNA) expression and fluorochrome staining with Mitotracker Red CMXRos (⌬⌿m) were decreased in cells expressing m53DD. Both alterations were specific for mitochondrial import competence (e.g., m53DD vs. c53DD) as well as the passenger protein (e.g., m53DD vs. mEGFP). The normal functional state of mitochondria was restored with PK11195, a specific ligand of the mitochondrial peripheral-type benzodiazepine receptor. Negative dominance of m53DD on 16S rRNA expression and CMXRos staining, and rescue of these parameters with PK11195, imply a direct positive effect of p53 on mitochondrial biogenesis and function.-Donahue, R.

Research paper thumbnail of CARD-8 Protein, a New CARD Family Member That Regulates Caspase-1 Activation and Apoptosis

Journal of Biological Chemistry, 2002

Caspase-associated recruitment domains (CARD) are protein-protein interaction modules found exten... more Caspase-associated recruitment domains (CARD) are protein-protein interaction modules found extensively in proteins that play important roles in apoptosis, NFB activation, and cytokine regulation. In this study we identified a novel human protein, CARD-8, which contains a C-terminal CARD domain with high similarity to the CARD domain of caspase-1/ICE. We demonstrate that CARD-8 interacts physically with caspase-1 and negatively regulates caspase-1-dependent IL-1␤ generation in the THP-1 monocytic cell line. CARD-8 binds also to ICEBERG and pseudo-ICE, two other recently identified proteins, which bind to the CARD domain of caspase-1 and negatively regulate its activity. Reverse transcriptase-PCR analysis revealed that CARD-8 is expressed mainly in monocytes, placenta, lymph nodes, and spleen. This pattern of expression is consistent with caspase-1 expression in the same cells and tissues. CARD-8 was also found to negatively regulate NF-B activation by TNF-␣ stimulation and by ectopically expressed RICK, suggesting that this protein may control cell survival. Consistent with these results, stable expression of CARD-8 in U937 or THP-1 cells sensitizes the cells to differentiation-induced apoptosis. Overexpression of CARD-8 can also induce apoptosis in transfected cells. The results suggest that CARD-8 represents a new signaling molecule involved in the regulation of caspase-1 and NF-B activation.

Research paper thumbnail of Identification of Ipaf, a Human Caspase-1-activating Protein Related to Apaf-1

Journal of Biological Chemistry, 2001

Research paper thumbnail of The PYRIN-CARD Protein ASC Is an Activating Adaptor for Caspase-1

Journal of Biological Chemistry, 2002

The PYRIN and CARD domains are members of the six-helix bundle death domain-fold superfamily that... more The PYRIN and CARD domains are members of the six-helix bundle death domain-fold superfamily that mediates assembly of large signaling complexes in the apoptotic and inflammatory signaling pathways. Here we show that the PYRIN-CARD protein ASC functions as a caspase-1-activating adaptor. ASC interacted specifically with procaspase-1 via CARD-CARD interactions and induced its oligomerization. Consistent with these results ectopic expression of full-length ASC, but not its isolated CARD or PYRIN domain, with procaspase-1 induced activation of procaspase-1 and processing of prointerleukin-1␤ in transfected cells. Substitution of the PYRIN domain of ASC with an inducible FKBP12 oligomerization domain produced a molecule that can induce caspase-1 activation in response to stimulation with the oligomerization drug AP20187, suggesting that the PYRIN domain functions as an oligomerization domain, whereas the CARD domain functions as the effector domain in the caspase-1 activation pathway. Furthermore stable expression of an isolated CARD of ASC in THP-1 cells diminished interleukin-1␤ generation in response to pro-inflammatory cytokines. These results indicate that ASC is involved in the caspase-1 signaling pathway by mediating the assembly of a caspase-1-inflammasome signaling complex in response to pro-inflammatory cytokine stimulation.

Research paper thumbnail of CTLA-4{middle dot}Ig converts naive CD4+CD25- T cells into CD4+CD25+ regulatory T cells

International Immunology, 2008

CTLA-4ÁIg was originally designed as an immunosuppressive agent capable of interfering with the c... more CTLA-4ÁIg was originally designed as an immunosuppressive agent capable of interfering with the co-stimulation of T cells. In the present study, we demonstrate that CTLA-4ÁIg, in combination with TCR ligation, has the additional capacity to convert naive CD4 1 CD25 2 T cells into Foxp3 1 regulatory T (T reg) cells, as well as to expand their numbers. The CD4 1 CD25 1 Foxp3 1 T reg generated by CTLA-4ÁIg treatment in vitro potently suppress effector T cells. Extending this in vivo, we show that systemic administration of CTLA-4ÁIg increases the percentage of CD4 1 CD25 hi Foxp3 1 cells within mixed lymphocyte reaction-induced murine lymph nodes. Significantly, the in vitro conversion of naive CD4 1 CD25 2 T cells into T reg cells is antigen-presenting cell (APC) dependent. This finding, together with the further observation that this conversion can also be driven in vitro by an antibody that engages B7-2 ligand, suggests that CTLA-4ÁIg-driven T reg induction may be predicated upon active CTLA-4ÁIg to B7-2 signaling within APC, which elicits from them T reg-inducing potential. These findings extend CTLA-4ÁIg's functional repertoire, and at the same time, reinforce the concept that T cell anergy and active suppression are not entirely distinct processes and may be linked by some common molecular triggers.

Research paper thumbnail of Regulation of IL-1β generation by Pseudo-ICE and ICEBERG, two dominant negative caspase recruitment domain proteins

Cell Death & Differentiation, 2001

We report here the identification and functional characterization of two new human caspase recrui... more We report here the identification and functional characterization of two new human caspase recruitment domain (CARD) molecules, termed Pseudo-interleukin-1b converting enzyme (ICE) and ICEBERG. Both proteins share a high degree of homology, reaching 92% and 53% identity, respectively, to the prodomain of caspase-1/ICE. Interestingly, both Pseudo-ICE and ICEBERG are mapped to chromosome 11q22 that bears caspases-1,-4-and-5 genes, all involved in cytokine production rather than in apoptosis. We demonstrate that Pseudo-ICE and ICEBERG interact physically with caspase-1 and block, in a monocytic cell line, the interferon-g and lipopolysaccharide-induced secretion of interleukin-1b which is a well-known consequence of caspase-1 activation. Moreover, Pseudo-ICE, but not ICEBERG, interacts with the CARD-containing kinase RICK/RIP2/CARDIAK and activates NF-kB. Our data suggest that Pseudo-ICE and ICEBERG are intracellular regulators of caspase-1 activation and could play a role in the regulation of IL-1b secretion and NF-kB activation during the pro-inflammatory cytokine response. Cell Death and Differentiation (2001) 8, 649 ± 657.

Research paper thumbnail of Altered expression of mitochondrial 16S ribosomal RNA in p53-deficient mouse embryos revealed by differential display

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 1998

Inactivation of the tumor suppressor p53 is associated with neural tube defects and altered terat... more Inactivation of the tumor suppressor p53 is associated with neural tube defects and altered teratogenicity in early embryos. To gain insight into the function of p53 during early embryogenesis, RNA profiles of wild-type p53(+/+) and p53(3/3) null mutant mouse embryos were compared at the head-fold stage (day 8 post coitum) using HPLC-based mRNA differential display. The results of this screen revealed a deficiency of mitochondrial 16S ribosomal RNA in p53(3/3) embryos. RT-PCR showed abnormalities in 16S rRNA levels relative to some representative nuclear (COIV, L-actin) and mitochondrial (COIII) transcripts in p53(3/3) embryos, and that 16S rRNA expression increased with development of p53(+/+) embryos during neurulation. Embryos that lack p53 also displayed weakened cytochrome c oxidase staining and reduced ATP content. During neurulation, the mouse embryo switches from an anaerobic (glycolytic) to an aerobic (oxidative) metabolism. The preliminary results of the present study suggest that p53 may be involved, directly or indirectly, in this transition.