The Experts below are selected from a list of 114972 Experts worldwide ranked by ideXlab platform
Elizabeth A Grimm - One of the best experts on this subject based on the ideXlab platform.
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human interleukin 24 mda 7 IL 24 protein kILls breast cancer cells via the IL 20 receptor and is antagonized by IL 10
Cancer Immunology Immunotherapy, 2006Co-Authors: Mingzhong Zheng, Kelly K Hunt, Nancy Poindexter, Rajagopal Ramesh, Bryan R Sutton, Dora Bocangel, Suhendan Ekmekcioglu, Blair Doneske, Abner M Mhashilkar, Elizabeth A GrimmAbstract:The melanoma differentiation-associated gene-7 (mda-7/IL-24) is a unique member of the interleukin 10 (IL-10) famILy of cytokines, with ubiquitous tumor cell pro-apoptotic activity. Recent data have shown that IL-24 is secreted as a glycosylated protein and functions as a pro-Th1 cytokine and as a potent anti-angiogenic molecule. In this study, we analyzed the activity of Ad-mda7 and its protein product, secreted IL-24, against human breast cancer cells. We show that Ad-mda7 transduction of human breast cancer cells results in G2/M phase cell cycle arrest and apoptotic cell death, which correlates with secretion of IL-24 protein. Neutralizing antibody against IL-24 significantly inhibited Ad-mda7 cytotoxicity. IL-24 and IL-10 both engage their cognate receptors on breast cancer cells resulting in phosphorylation and activation of STAT3, however, IL-10 receptor binding faILed to induce cell kILling, indicating that tumor cell kILling by IL-24 is independent of STAT3 phosphorylation. Treatment with exogenous IL-24 induced apoptosis in breast cancer cells and this effect was abolished by addition of anti-IL-24 antibody or anti-IL-20R1, indicating that bystander cell kILling is mediated via IL-24 binding to the IL-20R1/IL-20R2 heterodimeric receptor complex. Co-administration of the related cytokine IL-10 inhibited kILling mediated by IL-24 and concomitantly inhibited IL-24 mediated up-regulation of the tumor suppressor proteins, p53 and p27Kip1. In summary, we have defined a tumor-selective cytotoxic bystander role for secreted IL-24 protein and identified a novel receptor-mediated death pathway in breast cancer cells, wherein the related cytokines IL-24 and IL-10 exhibit antagonistic activity.
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771 human mda 7 interleukin 24 IL 24 protein kILls breast cancer cells via the IL 20 receptor and is antagonized by IL 10
Molecular Therapy, 2006Co-Authors: Minghong Zheng, Kelly K Hunt, Nancy Poindexter, Elizabeth A Grimm, Rajagopal Ramesh, Dora Bocangel, Suhendan Ekmekcioglu, Abner M Mhashilkar, Sunil ChadaAbstract:Top of pageAbstract The melanoma differentiation-associated gene-7 (mda-7/IL-24) is a unique member of the interleukin 10 (IL-10) famILy of cytokines, with ubiquitous tumor cell pro-apoptotic activity. Recent data have shown that IL-24 is secreted as a glycosylated protein and functions as a pro-Th1 cytokine and as a potent anti-angiogenic molecule. In this study, we analyzed the activity of Ad-mda7 and its protein product, secreted human IL-24, against human breast cancer cells. We show that Ad-mda7 transduction of breast cancer cells results in G2/M phase cell-cycle arrest and kILling, which correlates with secretion of IL-24 protein. Neutralizing antibody against IL-24 significantly inhibited Ad-mda7 kILling. IL-24 and IL-10 both engage their cognate receptors on breast cancer cells resulting in phosphorylation and activation of STAT3, however, IL-10 receptor binding faILed to induce cell kILling, indicating that tumor cell kILling by IL-24 is independent of STAT3 phosphorylation. Exogenous L-24 kILled breast cancer cells by induction of apoptosis and this effect was abolished by addition of anti-IL-24 antibody or anti-IL-20R1, indicating that bystander cell kILling is mediated via IL-24 binding to the IL-20R1/IL-20R2 heterodimeric receptor complex. Furthermore, IL-10 treatment inhibits kILling mediated by IL-24. In summary, we have defined a tumor-selective cytotoxic bystander role for secreted IL-24 protein and identified a novel receptor- mediated death pathway in breast cancer cells, wherein the related cytokines IL-24 and IL-10 exhibit antagonistic activity. SunIL Chada, Minghong Zheng, and Dora Bocangel are Introgen employees.
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cytokine induction of interleukin 24 in human peripheral blood mononuclear cells
Journal of Leukocyte Biology, 2005Co-Authors: Nancy Poindexter, Sunil Chada, Eugene T Walch, Elizabeth A GrimmAbstract:Interleukin-24 (IL-24) is a recently identified member of the IL-10 famILy of cytokines. It was originally identified as a tumor suppressor molecule, melanoma differentiation-associated gene 7, and then renamed IL-24 and classified as a cytokine, based on its chromosomal location in the IL-10 locus, its mRNA expression in leukocytes, and its secretory sequence elements. Here, we correlate the kinetics of IL-24 mRNA and protein expression in human peripheral blood mononuclear cells (PBMC) stimulated by polyclonal activators phytohemagglutinin (PHA) and lipopolysaccharide (LPS) or by allogeneic major histocompatibILity complex. PHA-stimulated PBMC express IL-24 mRNA, reaching peak levels at 8-12 h after stimulation. Protein expression, as measured by intracellular flow cytometry, followed the message, reaching maximum expression at 24 h. Subset analysis of mitogen-stimulated PBMC showed that IL-24 was expressed primarILy in T cells and macrophages. Expression of IL-24 in mitogen-stimulated PBMC is the result of cytokine stimulation. Individual cytokines including IL-2, IL-7, IL-15, tumor necrosis factor alpha, granulocyte macrophage-colony stimulating factor, and IL-1beta stimulate the expression of IL-24 mRNA and protein, whereas interferons and T helper cell type 2 cytokines faIL to induce substantial IL-24. When LPS- or PHA-stimulated cells were treated with Actinomycin D, IL-24 mRNA persisted at high levels over the 4-h course of treatment. These data strongly suggest that the expression of IL-24 in human PBMC results from cytokine stimulation and is regulated at the post-transcriptional level through stabILization of IL-24 mRNA.
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bystander activity of ad mda7 human mda 7 protein kILls melanoma cells via an IL 20 receptor dependent but stat3 independent mechanism
Molecular Therapy, 2004Co-Authors: Sunil Chada, Elizabeth A Grimm, Mingzhong Zheng, Rajagopal Ramesh, Bryan R Sutton, Dora Bocangel, Abner M Mhashilkar, John B Mumm, Suhendan EkmekciogluAbstract:The melanoma differentiation-associated gene-7 (mda-7/IL24) is a unique member of the IL-10 famILy of cytokines, with ubiquitous tumor cell proapoptotic activity. Transduction of tumor or normal cells with the mda-7 gene results in secretion of glycosylated MDA-7 protein. Recent data indicate that secreted MDA-7 protein functions as a pro-Th1 cytokine and as a potent antiangiogenic molecule. MDA-7 protein binds two distinct type II cytokine heterodimeric receptor complexes, IL-20R1/IL-20R2 (type 1 IL-20R) and IL-22R1/IL-20R2 (type 2 IL-20R). In this study we analyzed the activity of glycosylated secreted MDA-7 against human melanoma cells. MDA-7 protein induces phosphorylation and nuclear translocation of STAT3 in melanoma cells via both type 1 and type 2 IL-20R. MDA-7 induces dose-dependent cell death in melanoma tumor cells. MDA-7 receptor engagement results in up-regulation of BAX and subsequent apoptosis induction; this effect is mediated by STAT3-independent signaling. Additional IL-10 famILy members (IL-10, -19, -20, and -22) also activate STAT3; however, these ligands do not activate death pathways in melanoma. In normal cells, MDA-7 can bind to its cognate receptors and induce phosphorylation of STAT3, without cytotoxic sequelae. This study defines a tumor-selective cytotoxic bystander role for secreted MDA-7 protein and identifies a novel receptor-mediated, STAT3-independent, and PKR-independent death pathway.
Sunil Chada - One of the best experts on this subject based on the ideXlab platform.
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structural mapping of post translational modifications in human interleukin 24 role of n linked glycosylation and disulfide bonds in secretion and activity
Journal of Biological Chemistry, 2009Co-Authors: Kerry L Fuson, Abujiang Pataer, Sunil Chada, Mingzhong Zheng, Molly Craxton, Rajagopal Ramesh, Bryan R SuttonAbstract:Human interleukin-24 (IL-24) is unique among the IL-10 superfamILy as there is considerable evidence that it possesses multiple anti-cancer properties, including direct tumor cell cytotoxicity, helper T cell (TH1) immune stimulation, and anti-angiogenic activities. The primary sequence of human IL-24 differs from homologous cytokines, because it possesses three consensus N-linked glycosylation sites and the potential for a single disulfide bond. To address the significance of these modifications in human IL-24, we analyzed the relationship between post-translational modifications and the cytokine activity of the human IL-24 protein. In contrast to related interleukins, we identified a relationship between net glycosylation, protein solubILity, and cytokine activity. In addition, abrogation of the two cysteine residues by mutagenesis dramatically altered the abILity of IL-24 to secrete from host cells and resulted in the concomitant loss of IL-24 activity. We conclude that, unlike other IL-10 famILy members, human IL-24 must be glycosylated to maintain solubILity and bioavaILabILity. Further, a single, unique disulfide bond is required for secretion and activity. These structure-function relationships show that, although IL-24 is a member of the IL-19 subfamILy of IL-10-like cytokines by sequence simILarity, its surface properties and its distinctive disulfide arrangement make it unique. These observations could explain the novel biological activities measured of this cytokine. Understanding the structural basis of IL-24 activity wILl be important in the interpretation of the function of this cytokine and in the development of scale-up strategies for biophysical and clinical applications.
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771 human mda 7 interleukin 24 IL 24 protein kILls breast cancer cells via the IL 20 receptor and is antagonized by IL 10
Molecular Therapy, 2006Co-Authors: Minghong Zheng, Kelly K Hunt, Nancy Poindexter, Elizabeth A Grimm, Rajagopal Ramesh, Dora Bocangel, Suhendan Ekmekcioglu, Abner M Mhashilkar, Sunil ChadaAbstract:Top of pageAbstract The melanoma differentiation-associated gene-7 (mda-7/IL-24) is a unique member of the interleukin 10 (IL-10) famILy of cytokines, with ubiquitous tumor cell pro-apoptotic activity. Recent data have shown that IL-24 is secreted as a glycosylated protein and functions as a pro-Th1 cytokine and as a potent anti-angiogenic molecule. In this study, we analyzed the activity of Ad-mda7 and its protein product, secreted human IL-24, against human breast cancer cells. We show that Ad-mda7 transduction of breast cancer cells results in G2/M phase cell-cycle arrest and kILling, which correlates with secretion of IL-24 protein. Neutralizing antibody against IL-24 significantly inhibited Ad-mda7 kILling. IL-24 and IL-10 both engage their cognate receptors on breast cancer cells resulting in phosphorylation and activation of STAT3, however, IL-10 receptor binding faILed to induce cell kILling, indicating that tumor cell kILling by IL-24 is independent of STAT3 phosphorylation. Exogenous L-24 kILled breast cancer cells by induction of apoptosis and this effect was abolished by addition of anti-IL-24 antibody or anti-IL-20R1, indicating that bystander cell kILling is mediated via IL-24 binding to the IL-20R1/IL-20R2 heterodimeric receptor complex. Furthermore, IL-10 treatment inhibits kILling mediated by IL-24. In summary, we have defined a tumor-selective cytotoxic bystander role for secreted IL-24 protein and identified a novel receptor- mediated death pathway in breast cancer cells, wherein the related cytokines IL-24 and IL-10 exhibit antagonistic activity. SunIL Chada, Minghong Zheng, and Dora Bocangel are Introgen employees.
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cytokine induction of interleukin 24 in human peripheral blood mononuclear cells
Journal of Leukocyte Biology, 2005Co-Authors: Nancy Poindexter, Sunil Chada, Eugene T Walch, Elizabeth A GrimmAbstract:Interleukin-24 (IL-24) is a recently identified member of the IL-10 famILy of cytokines. It was originally identified as a tumor suppressor molecule, melanoma differentiation-associated gene 7, and then renamed IL-24 and classified as a cytokine, based on its chromosomal location in the IL-10 locus, its mRNA expression in leukocytes, and its secretory sequence elements. Here, we correlate the kinetics of IL-24 mRNA and protein expression in human peripheral blood mononuclear cells (PBMC) stimulated by polyclonal activators phytohemagglutinin (PHA) and lipopolysaccharide (LPS) or by allogeneic major histocompatibILity complex. PHA-stimulated PBMC express IL-24 mRNA, reaching peak levels at 8-12 h after stimulation. Protein expression, as measured by intracellular flow cytometry, followed the message, reaching maximum expression at 24 h. Subset analysis of mitogen-stimulated PBMC showed that IL-24 was expressed primarILy in T cells and macrophages. Expression of IL-24 in mitogen-stimulated PBMC is the result of cytokine stimulation. Individual cytokines including IL-2, IL-7, IL-15, tumor necrosis factor alpha, granulocyte macrophage-colony stimulating factor, and IL-1beta stimulate the expression of IL-24 mRNA and protein, whereas interferons and T helper cell type 2 cytokines faIL to induce substantial IL-24. When LPS- or PHA-stimulated cells were treated with Actinomycin D, IL-24 mRNA persisted at high levels over the 4-h course of treatment. These data strongly suggest that the expression of IL-24 in human PBMC results from cytokine stimulation and is regulated at the post-transcriptional level through stabILization of IL-24 mRNA.
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bystander activity of ad mda7 human mda 7 protein kILls melanoma cells via an IL 20 receptor dependent but stat3 independent mechanism
Molecular Therapy, 2004Co-Authors: Sunil Chada, Elizabeth A Grimm, Mingzhong Zheng, Rajagopal Ramesh, Bryan R Sutton, Dora Bocangel, Abner M Mhashilkar, John B Mumm, Suhendan EkmekciogluAbstract:The melanoma differentiation-associated gene-7 (mda-7/IL24) is a unique member of the IL-10 famILy of cytokines, with ubiquitous tumor cell proapoptotic activity. Transduction of tumor or normal cells with the mda-7 gene results in secretion of glycosylated MDA-7 protein. Recent data indicate that secreted MDA-7 protein functions as a pro-Th1 cytokine and as a potent antiangiogenic molecule. MDA-7 protein binds two distinct type II cytokine heterodimeric receptor complexes, IL-20R1/IL-20R2 (type 1 IL-20R) and IL-22R1/IL-20R2 (type 2 IL-20R). In this study we analyzed the activity of glycosylated secreted MDA-7 against human melanoma cells. MDA-7 protein induces phosphorylation and nuclear translocation of STAT3 in melanoma cells via both type 1 and type 2 IL-20R. MDA-7 induces dose-dependent cell death in melanoma tumor cells. MDA-7 receptor engagement results in up-regulation of BAX and subsequent apoptosis induction; this effect is mediated by STAT3-independent signaling. Additional IL-10 famILy members (IL-10, -19, -20, and -22) also activate STAT3; however, these ligands do not activate death pathways in melanoma. In normal cells, MDA-7 can bind to its cognate receptors and induce phosphorylation of STAT3, without cytotoxic sequelae. This study defines a tumor-selective cytotoxic bystander role for secreted MDA-7 protein and identifies a novel receptor-mediated, STAT3-independent, and PKR-independent death pathway.
Rajagopal Ramesh - One of the best experts on this subject based on the ideXlab platform.
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interleukin IL 24 reconfiguring the tumor microenvironment for eliciting antitumor response
Advances in Experimental Medicine and Biology, 2021Co-Authors: Rajagopal Ramesh, Rebaz Ahmed, Anupama MunshiAbstract:Interleukin (IL)-24 is a member of the IL-10 famILy of cytokines. Due to its unique abILity to function as both a tumor suppressor and cytokine, IL-24-based cancer therapy has been developed for treating a broad spectrum of human cancers. Majority of the studies reported to date have focused on establishing IL-24 as a cancer therapeutic by primarILy focusing on tumor cell kILling. However, the abILity of IL-24 treatment on modulating the tumor microenvironment and immune response is underinvestigated. In this article, we summarize the biological and functional properties of IL-24 and the benefits of applying IL-24-based therapy for cancer.
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structural mapping of post translational modifications in human interleukin 24 role of n linked glycosylation and disulfide bonds in secretion and activity
Journal of Biological Chemistry, 2009Co-Authors: Kerry L Fuson, Abujiang Pataer, Sunil Chada, Mingzhong Zheng, Molly Craxton, Rajagopal Ramesh, Bryan R SuttonAbstract:Human interleukin-24 (IL-24) is unique among the IL-10 superfamILy as there is considerable evidence that it possesses multiple anti-cancer properties, including direct tumor cell cytotoxicity, helper T cell (TH1) immune stimulation, and anti-angiogenic activities. The primary sequence of human IL-24 differs from homologous cytokines, because it possesses three consensus N-linked glycosylation sites and the potential for a single disulfide bond. To address the significance of these modifications in human IL-24, we analyzed the relationship between post-translational modifications and the cytokine activity of the human IL-24 protein. In contrast to related interleukins, we identified a relationship between net glycosylation, protein solubILity, and cytokine activity. In addition, abrogation of the two cysteine residues by mutagenesis dramatically altered the abILity of IL-24 to secrete from host cells and resulted in the concomitant loss of IL-24 activity. We conclude that, unlike other IL-10 famILy members, human IL-24 must be glycosylated to maintain solubILity and bioavaILabILity. Further, a single, unique disulfide bond is required for secretion and activity. These structure-function relationships show that, although IL-24 is a member of the IL-19 subfamILy of IL-10-like cytokines by sequence simILarity, its surface properties and its distinctive disulfide arrangement make it unique. These observations could explain the novel biological activities measured of this cytokine. Understanding the structural basis of IL-24 activity wILl be important in the interpretation of the function of this cytokine and in the development of scale-up strategies for biophysical and clinical applications.
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human interleukin 24 mda 7 IL 24 protein kILls breast cancer cells via the IL 20 receptor and is antagonized by IL 10
Cancer Immunology Immunotherapy, 2006Co-Authors: Mingzhong Zheng, Kelly K Hunt, Nancy Poindexter, Rajagopal Ramesh, Bryan R Sutton, Dora Bocangel, Suhendan Ekmekcioglu, Blair Doneske, Abner M Mhashilkar, Elizabeth A GrimmAbstract:The melanoma differentiation-associated gene-7 (mda-7/IL-24) is a unique member of the interleukin 10 (IL-10) famILy of cytokines, with ubiquitous tumor cell pro-apoptotic activity. Recent data have shown that IL-24 is secreted as a glycosylated protein and functions as a pro-Th1 cytokine and as a potent anti-angiogenic molecule. In this study, we analyzed the activity of Ad-mda7 and its protein product, secreted IL-24, against human breast cancer cells. We show that Ad-mda7 transduction of human breast cancer cells results in G2/M phase cell cycle arrest and apoptotic cell death, which correlates with secretion of IL-24 protein. Neutralizing antibody against IL-24 significantly inhibited Ad-mda7 cytotoxicity. IL-24 and IL-10 both engage their cognate receptors on breast cancer cells resulting in phosphorylation and activation of STAT3, however, IL-10 receptor binding faILed to induce cell kILling, indicating that tumor cell kILling by IL-24 is independent of STAT3 phosphorylation. Treatment with exogenous IL-24 induced apoptosis in breast cancer cells and this effect was abolished by addition of anti-IL-24 antibody or anti-IL-20R1, indicating that bystander cell kILling is mediated via IL-24 binding to the IL-20R1/IL-20R2 heterodimeric receptor complex. Co-administration of the related cytokine IL-10 inhibited kILling mediated by IL-24 and concomitantly inhibited IL-24 mediated up-regulation of the tumor suppressor proteins, p53 and p27Kip1. In summary, we have defined a tumor-selective cytotoxic bystander role for secreted IL-24 protein and identified a novel receptor-mediated death pathway in breast cancer cells, wherein the related cytokines IL-24 and IL-10 exhibit antagonistic activity.
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771 human mda 7 interleukin 24 IL 24 protein kILls breast cancer cells via the IL 20 receptor and is antagonized by IL 10
Molecular Therapy, 2006Co-Authors: Minghong Zheng, Kelly K Hunt, Nancy Poindexter, Elizabeth A Grimm, Rajagopal Ramesh, Dora Bocangel, Suhendan Ekmekcioglu, Abner M Mhashilkar, Sunil ChadaAbstract:Top of pageAbstract The melanoma differentiation-associated gene-7 (mda-7/IL-24) is a unique member of the interleukin 10 (IL-10) famILy of cytokines, with ubiquitous tumor cell pro-apoptotic activity. Recent data have shown that IL-24 is secreted as a glycosylated protein and functions as a pro-Th1 cytokine and as a potent anti-angiogenic molecule. In this study, we analyzed the activity of Ad-mda7 and its protein product, secreted human IL-24, against human breast cancer cells. We show that Ad-mda7 transduction of breast cancer cells results in G2/M phase cell-cycle arrest and kILling, which correlates with secretion of IL-24 protein. Neutralizing antibody against IL-24 significantly inhibited Ad-mda7 kILling. IL-24 and IL-10 both engage their cognate receptors on breast cancer cells resulting in phosphorylation and activation of STAT3, however, IL-10 receptor binding faILed to induce cell kILling, indicating that tumor cell kILling by IL-24 is independent of STAT3 phosphorylation. Exogenous L-24 kILled breast cancer cells by induction of apoptosis and this effect was abolished by addition of anti-IL-24 antibody or anti-IL-20R1, indicating that bystander cell kILling is mediated via IL-24 binding to the IL-20R1/IL-20R2 heterodimeric receptor complex. Furthermore, IL-10 treatment inhibits kILling mediated by IL-24. In summary, we have defined a tumor-selective cytotoxic bystander role for secreted IL-24 protein and identified a novel receptor- mediated death pathway in breast cancer cells, wherein the related cytokines IL-24 and IL-10 exhibit antagonistic activity. SunIL Chada, Minghong Zheng, and Dora Bocangel are Introgen employees.
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bystander activity of ad mda7 human mda 7 protein kILls melanoma cells via an IL 20 receptor dependent but stat3 independent mechanism
Molecular Therapy, 2004Co-Authors: Sunil Chada, Elizabeth A Grimm, Mingzhong Zheng, Rajagopal Ramesh, Bryan R Sutton, Dora Bocangel, Abner M Mhashilkar, John B Mumm, Suhendan EkmekciogluAbstract:The melanoma differentiation-associated gene-7 (mda-7/IL24) is a unique member of the IL-10 famILy of cytokines, with ubiquitous tumor cell proapoptotic activity. Transduction of tumor or normal cells with the mda-7 gene results in secretion of glycosylated MDA-7 protein. Recent data indicate that secreted MDA-7 protein functions as a pro-Th1 cytokine and as a potent antiangiogenic molecule. MDA-7 protein binds two distinct type II cytokine heterodimeric receptor complexes, IL-20R1/IL-20R2 (type 1 IL-20R) and IL-22R1/IL-20R2 (type 2 IL-20R). In this study we analyzed the activity of glycosylated secreted MDA-7 against human melanoma cells. MDA-7 protein induces phosphorylation and nuclear translocation of STAT3 in melanoma cells via both type 1 and type 2 IL-20R. MDA-7 induces dose-dependent cell death in melanoma tumor cells. MDA-7 receptor engagement results in up-regulation of BAX and subsequent apoptosis induction; this effect is mediated by STAT3-independent signaling. Additional IL-10 famILy members (IL-10, -19, -20, and -22) also activate STAT3; however, these ligands do not activate death pathways in melanoma. In normal cells, MDA-7 can bind to its cognate receptors and induce phosphorylation of STAT3, without cytotoxic sequelae. This study defines a tumor-selective cytotoxic bystander role for secreted MDA-7 protein and identifies a novel receptor-mediated, STAT3-independent, and PKR-independent death pathway.
Suhendan Ekmekcioglu - One of the best experts on this subject based on the ideXlab platform.
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human interleukin 24 mda 7 IL 24 protein kILls breast cancer cells via the IL 20 receptor and is antagonized by IL 10
Cancer Immunology Immunotherapy, 2006Co-Authors: Mingzhong Zheng, Kelly K Hunt, Nancy Poindexter, Rajagopal Ramesh, Bryan R Sutton, Dora Bocangel, Suhendan Ekmekcioglu, Blair Doneske, Abner M Mhashilkar, Elizabeth A GrimmAbstract:The melanoma differentiation-associated gene-7 (mda-7/IL-24) is a unique member of the interleukin 10 (IL-10) famILy of cytokines, with ubiquitous tumor cell pro-apoptotic activity. Recent data have shown that IL-24 is secreted as a glycosylated protein and functions as a pro-Th1 cytokine and as a potent anti-angiogenic molecule. In this study, we analyzed the activity of Ad-mda7 and its protein product, secreted IL-24, against human breast cancer cells. We show that Ad-mda7 transduction of human breast cancer cells results in G2/M phase cell cycle arrest and apoptotic cell death, which correlates with secretion of IL-24 protein. Neutralizing antibody against IL-24 significantly inhibited Ad-mda7 cytotoxicity. IL-24 and IL-10 both engage their cognate receptors on breast cancer cells resulting in phosphorylation and activation of STAT3, however, IL-10 receptor binding faILed to induce cell kILling, indicating that tumor cell kILling by IL-24 is independent of STAT3 phosphorylation. Treatment with exogenous IL-24 induced apoptosis in breast cancer cells and this effect was abolished by addition of anti-IL-24 antibody or anti-IL-20R1, indicating that bystander cell kILling is mediated via IL-24 binding to the IL-20R1/IL-20R2 heterodimeric receptor complex. Co-administration of the related cytokine IL-10 inhibited kILling mediated by IL-24 and concomitantly inhibited IL-24 mediated up-regulation of the tumor suppressor proteins, p53 and p27Kip1. In summary, we have defined a tumor-selective cytotoxic bystander role for secreted IL-24 protein and identified a novel receptor-mediated death pathway in breast cancer cells, wherein the related cytokines IL-24 and IL-10 exhibit antagonistic activity.
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771 human mda 7 interleukin 24 IL 24 protein kILls breast cancer cells via the IL 20 receptor and is antagonized by IL 10
Molecular Therapy, 2006Co-Authors: Minghong Zheng, Kelly K Hunt, Nancy Poindexter, Elizabeth A Grimm, Rajagopal Ramesh, Dora Bocangel, Suhendan Ekmekcioglu, Abner M Mhashilkar, Sunil ChadaAbstract:Top of pageAbstract The melanoma differentiation-associated gene-7 (mda-7/IL-24) is a unique member of the interleukin 10 (IL-10) famILy of cytokines, with ubiquitous tumor cell pro-apoptotic activity. Recent data have shown that IL-24 is secreted as a glycosylated protein and functions as a pro-Th1 cytokine and as a potent anti-angiogenic molecule. In this study, we analyzed the activity of Ad-mda7 and its protein product, secreted human IL-24, against human breast cancer cells. We show that Ad-mda7 transduction of breast cancer cells results in G2/M phase cell-cycle arrest and kILling, which correlates with secretion of IL-24 protein. Neutralizing antibody against IL-24 significantly inhibited Ad-mda7 kILling. IL-24 and IL-10 both engage their cognate receptors on breast cancer cells resulting in phosphorylation and activation of STAT3, however, IL-10 receptor binding faILed to induce cell kILling, indicating that tumor cell kILling by IL-24 is independent of STAT3 phosphorylation. Exogenous L-24 kILled breast cancer cells by induction of apoptosis and this effect was abolished by addition of anti-IL-24 antibody or anti-IL-20R1, indicating that bystander cell kILling is mediated via IL-24 binding to the IL-20R1/IL-20R2 heterodimeric receptor complex. Furthermore, IL-10 treatment inhibits kILling mediated by IL-24. In summary, we have defined a tumor-selective cytotoxic bystander role for secreted IL-24 protein and identified a novel receptor- mediated death pathway in breast cancer cells, wherein the related cytokines IL-24 and IL-10 exhibit antagonistic activity. SunIL Chada, Minghong Zheng, and Dora Bocangel are Introgen employees.
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bystander activity of ad mda7 human mda 7 protein kILls melanoma cells via an IL 20 receptor dependent but stat3 independent mechanism
Molecular Therapy, 2004Co-Authors: Sunil Chada, Elizabeth A Grimm, Mingzhong Zheng, Rajagopal Ramesh, Bryan R Sutton, Dora Bocangel, Abner M Mhashilkar, John B Mumm, Suhendan EkmekciogluAbstract:The melanoma differentiation-associated gene-7 (mda-7/IL24) is a unique member of the IL-10 famILy of cytokines, with ubiquitous tumor cell proapoptotic activity. Transduction of tumor or normal cells with the mda-7 gene results in secretion of glycosylated MDA-7 protein. Recent data indicate that secreted MDA-7 protein functions as a pro-Th1 cytokine and as a potent antiangiogenic molecule. MDA-7 protein binds two distinct type II cytokine heterodimeric receptor complexes, IL-20R1/IL-20R2 (type 1 IL-20R) and IL-22R1/IL-20R2 (type 2 IL-20R). In this study we analyzed the activity of glycosylated secreted MDA-7 against human melanoma cells. MDA-7 protein induces phosphorylation and nuclear translocation of STAT3 in melanoma cells via both type 1 and type 2 IL-20R. MDA-7 induces dose-dependent cell death in melanoma tumor cells. MDA-7 receptor engagement results in up-regulation of BAX and subsequent apoptosis induction; this effect is mediated by STAT3-independent signaling. Additional IL-10 famILy members (IL-10, -19, -20, and -22) also activate STAT3; however, these ligands do not activate death pathways in melanoma. In normal cells, MDA-7 can bind to its cognate receptors and induce phosphorylation of STAT3, without cytotoxic sequelae. This study defines a tumor-selective cytotoxic bystander role for secreted MDA-7 protein and identifies a novel receptor-mediated, STAT3-independent, and PKR-independent death pathway.
Mingzhong Zheng - One of the best experts on this subject based on the ideXlab platform.
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structural mapping of post translational modifications in human interleukin 24 role of n linked glycosylation and disulfide bonds in secretion and activity
Journal of Biological Chemistry, 2009Co-Authors: Kerry L Fuson, Abujiang Pataer, Sunil Chada, Mingzhong Zheng, Molly Craxton, Rajagopal Ramesh, Bryan R SuttonAbstract:Human interleukin-24 (IL-24) is unique among the IL-10 superfamILy as there is considerable evidence that it possesses multiple anti-cancer properties, including direct tumor cell cytotoxicity, helper T cell (TH1) immune stimulation, and anti-angiogenic activities. The primary sequence of human IL-24 differs from homologous cytokines, because it possesses three consensus N-linked glycosylation sites and the potential for a single disulfide bond. To address the significance of these modifications in human IL-24, we analyzed the relationship between post-translational modifications and the cytokine activity of the human IL-24 protein. In contrast to related interleukins, we identified a relationship between net glycosylation, protein solubILity, and cytokine activity. In addition, abrogation of the two cysteine residues by mutagenesis dramatically altered the abILity of IL-24 to secrete from host cells and resulted in the concomitant loss of IL-24 activity. We conclude that, unlike other IL-10 famILy members, human IL-24 must be glycosylated to maintain solubILity and bioavaILabILity. Further, a single, unique disulfide bond is required for secretion and activity. These structure-function relationships show that, although IL-24 is a member of the IL-19 subfamILy of IL-10-like cytokines by sequence simILarity, its surface properties and its distinctive disulfide arrangement make it unique. These observations could explain the novel biological activities measured of this cytokine. Understanding the structural basis of IL-24 activity wILl be important in the interpretation of the function of this cytokine and in the development of scale-up strategies for biophysical and clinical applications.
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human interleukin 24 mda 7 IL 24 protein kILls breast cancer cells via the IL 20 receptor and is antagonized by IL 10
Cancer Immunology Immunotherapy, 2006Co-Authors: Mingzhong Zheng, Kelly K Hunt, Nancy Poindexter, Rajagopal Ramesh, Bryan R Sutton, Dora Bocangel, Suhendan Ekmekcioglu, Blair Doneske, Abner M Mhashilkar, Elizabeth A GrimmAbstract:The melanoma differentiation-associated gene-7 (mda-7/IL-24) is a unique member of the interleukin 10 (IL-10) famILy of cytokines, with ubiquitous tumor cell pro-apoptotic activity. Recent data have shown that IL-24 is secreted as a glycosylated protein and functions as a pro-Th1 cytokine and as a potent anti-angiogenic molecule. In this study, we analyzed the activity of Ad-mda7 and its protein product, secreted IL-24, against human breast cancer cells. We show that Ad-mda7 transduction of human breast cancer cells results in G2/M phase cell cycle arrest and apoptotic cell death, which correlates with secretion of IL-24 protein. Neutralizing antibody against IL-24 significantly inhibited Ad-mda7 cytotoxicity. IL-24 and IL-10 both engage their cognate receptors on breast cancer cells resulting in phosphorylation and activation of STAT3, however, IL-10 receptor binding faILed to induce cell kILling, indicating that tumor cell kILling by IL-24 is independent of STAT3 phosphorylation. Treatment with exogenous IL-24 induced apoptosis in breast cancer cells and this effect was abolished by addition of anti-IL-24 antibody or anti-IL-20R1, indicating that bystander cell kILling is mediated via IL-24 binding to the IL-20R1/IL-20R2 heterodimeric receptor complex. Co-administration of the related cytokine IL-10 inhibited kILling mediated by IL-24 and concomitantly inhibited IL-24 mediated up-regulation of the tumor suppressor proteins, p53 and p27Kip1. In summary, we have defined a tumor-selective cytotoxic bystander role for secreted IL-24 protein and identified a novel receptor-mediated death pathway in breast cancer cells, wherein the related cytokines IL-24 and IL-10 exhibit antagonistic activity.
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bystander activity of ad mda7 human mda 7 protein kILls melanoma cells via an IL 20 receptor dependent but stat3 independent mechanism
Molecular Therapy, 2004Co-Authors: Sunil Chada, Elizabeth A Grimm, Mingzhong Zheng, Rajagopal Ramesh, Bryan R Sutton, Dora Bocangel, Abner M Mhashilkar, John B Mumm, Suhendan EkmekciogluAbstract:The melanoma differentiation-associated gene-7 (mda-7/IL24) is a unique member of the IL-10 famILy of cytokines, with ubiquitous tumor cell proapoptotic activity. Transduction of tumor or normal cells with the mda-7 gene results in secretion of glycosylated MDA-7 protein. Recent data indicate that secreted MDA-7 protein functions as a pro-Th1 cytokine and as a potent antiangiogenic molecule. MDA-7 protein binds two distinct type II cytokine heterodimeric receptor complexes, IL-20R1/IL-20R2 (type 1 IL-20R) and IL-22R1/IL-20R2 (type 2 IL-20R). In this study we analyzed the activity of glycosylated secreted MDA-7 against human melanoma cells. MDA-7 protein induces phosphorylation and nuclear translocation of STAT3 in melanoma cells via both type 1 and type 2 IL-20R. MDA-7 induces dose-dependent cell death in melanoma tumor cells. MDA-7 receptor engagement results in up-regulation of BAX and subsequent apoptosis induction; this effect is mediated by STAT3-independent signaling. Additional IL-10 famILy members (IL-10, -19, -20, and -22) also activate STAT3; however, these ligands do not activate death pathways in melanoma. In normal cells, MDA-7 can bind to its cognate receptors and induce phosphorylation of STAT3, without cytotoxic sequelae. This study defines a tumor-selective cytotoxic bystander role for secreted MDA-7 protein and identifies a novel receptor-mediated, STAT3-independent, and PKR-independent death pathway.
