137 results on '"Rabson, Arnold B."'
Search Results
102. HIV-1 Infection of First-Trimester and Placental Tissue
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MAURY, WENDY, primary, POTS, BARBARA J., additional, and RABSON, ARNOLD B., additional
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- 1990
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103. Drug Targeting of HIV-1 RNA-DNA Hybrid Structures: Thermodynamic of Recognition and Impact on Reverse Transcriptase-Mediated Ribonuclease H Activity and Viral Replication.
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Tsai-Kun Li, Barbieri, Christopher M., Hsin-Chin Lin, Rabson, Arnold B., Gengcheng Yang, Fany, Yupeng, Gaffney, Barbara L., Jonesy, Roger A., and Pilch, Daniel S.
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- 2004
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104. The tumor suppressor gene WWOXlinks the canonical and noncanonical NF-κB pathways in HTLV-I Tax-mediated tumorigenesis
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Fu, Jing, Qu, Zhaoxia, Yan, Pengrong, Ishikawa, Chie, Aqeilan, Rami I., Rabson, Arnold B., and Xiao, Gutian
- Abstract
Both the canonical and noncanonical nuclear factor κB (NF-κB) pathways have been linked to tumorigenesis. However, it remains unknown whether and how the 2 signaling pathways cooperate during tumorigenesis. We report that inhibition of the noncanonical NF-κB pathway significantly delays tumorigenesis mediated by the viral oncoprotein Tax. One function of noncanonical NF-κB activation was to repress expression of the WWOXtumor suppressor gene. Notably, WWOX specifically inhibited Tax-induced activation of the canonical, but not the noncanonical NF-κB pathway. Mechanistic studies indicated that WWOX blocked Tax-induced inhibitors of κB kinaseα (IKKα) recruitment to RelA and subsequent RelA phosphorylation at S536. In contrast, WWOX Y33R, a mutant unable to block the IKKα recruitment and RelA phosphorylation, lost the ability to inhibit Tax-mediated tumorigenesis. These data provide one important mechanism by which Tax coordinates the 2 NF-κB pathways for tumorigenesis. These data also suggest a novel role of WWOX in NF-κB regulation and viral tumorigenesis.
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- 2011
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105. Tumorigenicity of T24 urinary bladder carcinoma cell sublines.
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Flatow, Ursula, Rabson, Arnold B., and Rabson, Alan S.
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- 1987
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106. mRNA transcripts related to full-length endogenous retroviral DNA in human cells.
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Rabson, Arnold B., Steele, Paul E., Garon, Claude F., and Martin, Malcolm A.
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- 1983
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107. Inhibitory effects of 12-O-tetradecanoylphorbol-13-acetate alone or in combination with all-trans retinoic acid on the growth of cultured human pancreas cancer cells and pancreas tumor xenografts in immunodeficient mice.
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Avila, Gina E, Zheng, Xi, Cui, Xiao Xing, Ryan, Amanda D, Hansson, Annette, Suh, Junghan, Rabson, Arnold B, Chang, Richard L, Shih, Weichung Joe, Lin, Yong, Crowell, Pamela, Lu, Yao Ping, Lou, You Rong, and Conney, Allan H
- Abstract
Treatment of cultured PANC-1, MIA PaCa-2, and BxPC-3 human pancreatic adenocarcinoma cells with 0.1 to 1.6 nM 12-O-tetradecanoylphorbol-13-acetate (TPA) for 96 h inhibited the proliferation of these cells in a dose-dependent manner, and PANC-1 and MIA PaCa-2 cells were more sensitive to TPA than BxPC-3 cells. Inhibition of proliferation by TPA in PANC-1 cells was associated with an increase in the level of p21, but this was not observed in MIA PaCa-2 or BxPC-3 cells. The TPA-induced increase of p21 in PANC-1 cells was blocked by bisindolylmaleimide or rottlerin (inhibitors of protein kinase C). Studies in NCr-immunodeficient mice with well established PANC-1 tumor xenografts indicated that daily i.p. injections of TPA strongly inhibited tumor growth, increased the percentage of caspase-3-positive cells, and decreased the ratio of mitotic cells to caspase-3-positive cells in the tumors. Studies with BxPC-3 tumors in NCr mice receiving daily i.p. injections of vehicle, TPA, all-trans retinoic acid (ATRA), or a TPA/ATRA combination showed that TPA had an inhibitory effect on tumor growth, but treatment of the animals with the TPA/ATRA combination had a greater inhibitory effect on tumor growth than TPA alone. Treatment with the TPA/ATRA combination resulted in a substantially decreased ratio of the percentage of mitotic cells to the percentage of caspase-3-positive cells in the tumors compared with tumors from the vehicle-treated control animals. The inhibitory effects of TPA on tumor growth occurred at clinically achievable blood levels.
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- 2005
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108. Activation of Human T-Cell Leukemia Virus Type 1taxGene Expression in Chronically Infected T Cells
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Lin, Hsin-Ching, Dezzutti, Charlene S., Lal, Renu B., and Rabson, Arnold B.
- Abstract
ABSTRACTExpression of human T-cell leukemia virus type 1 (HTLV-1) is regulated both by the HTLV-1 Tax transactivator and by cellular transcriptional factors binding to the viral long terminal repeat (LTR), suggesting that cellular signals may play a role in regulating viral expression. Treatment of cells chronically infected with HTLV-1, which express low levels of HTLV-1 RNAs and Tax protein, with phorbol esters (i.e., phorbol12-myristate 13-?acetate [PMA]), phytohemagglutinin (PHA), sodium butyrate, or combinations of cytokines resulted in induction of HTLV-?1 gene expression. PMA or PHA treatment following cotransfection of HTLV-1 Tax expression plasmids resulted in synergistic activation of HTLV-1 LTR-directed gene expression, apparently involving tyrosine ki- nase-?mediated pathways. These results suggest that cellular activation stimuli may cooperate with HTLV-1 Tax to enhance expression of integrated HTLV-1 genomes and thus may play a role in the pathogenesis of HTLV-1 disease.
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- 1998
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109. Metastasis to the submandibular gland as the initial presentation of small cell (“oat cell”) lung carcinoma
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Brodsky, Gilbert, primary and Rabson, Arnold B., additional
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- 1984
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110. Molecular pathogenesis of human immunodeficiency virus infection
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Rabson, Arnold B., primary, Koenig, Scott, additional, Daugherty, Daryl F., additional, and Gendelman, Howard E., additional
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- 1988
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111. Characterization and Tumorigenicity of a Butyrate-Adapted T24 Bladder Cancer Cell Line
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Flatow, Ursula, primary, Rabson, Arnold B., additional, Hand, Patricia H., additional, Willingham, Mark C., additional, and Rabson, Alan S., additional
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- 1989
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112. Giant cell myocarditis after mitral valve replacement: Case report and studies of the nature of giant cells
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Rabson, Arnold B., primary, Schoen, Frederick J., additional, Warhol, Michael J., additional, Mudge, Gilbert H., additional, and Collins, John J., additional
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- 1984
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113. Coordination of the canonical and noncanonical IKK/NF-κB signaling pathways in HTLV-I Taxmediated tumorigenesis.
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Jing Fu, Zhaoxia Qu, Pengrong Yan, Shirong Li, Xinxin Song, Chie Ishikawa, Aqeilan, Rami I., Mori, Naoki, Rabson, Arnold B., and Gutian Xiao
- Subjects
HTLV-I ,CARCINOGENESIS ,NF-kappa B - Abstract
An abstract of the research paper titled,"Coordination of the canonical and noncanonical IKK/NF-kB signaling pathways in the Human T-cell leukemia virus type 1 (HTLV-1) Taxmediated tumorigenesis," is presented.
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- 2011
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114. Activation of HTLV-1 expression in chronically-infected CD4+ T cells: mechanisms and implications for pathogenesis.
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Alison Swaims, Hsin-Ching Lin, Simon, Peter, Granier, Celine, Yingyu Zhang, Roberts, Arthur, Devadas, Satish, Yufang Shi, and Rabson, Arnold B.
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HTLV-I ,T cells - Abstract
An abstract of the research paper titled " Activation of HTLV-1 Expression in Chronically-Infected CD4+ T cells: Mechanisms and Implications for Pathogenesis," by Alison Swaims, Hsin-Ching Lin, Peter Simon, Celine Granier, Yingyu Zhang, Arthur Roberts and Satish Devadas is presented.
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- 2011
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115. Regulation of the Expression and Activity of the Antiangiogenic Homeobox Gene GAX/MEOX2 by ZEB2 and MicroRNA-221.
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Yun Chen, Banda, Malathi, Speyer, Cecilia L., Smith, Jennifer S., Rabson, Arnold B., and Gorski, David H.
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RNA ,HOMEOBOX genes ,CHROMATIN ,PROMOTERS (Genetics) ,NEOVASCULARIZATION - Abstract
Tumors secrete proangiogenic factors to induce the ingrowth of blood vessels from the stroma. These peptides bind to cell surface receptors on vascular endothelial cells (ECs), triggering signaling cascades that activate and repress batteries of downstream genes responsible for the angiogenic phenotype. To determine if microRNAs (miRNAs) affect regulation of the EC phenotype by GAX, a homeobox gene and negative transcriptional regulator of the angiogenic phenotype, we tested the effect of miR-221 on GAX expression. miR-221 strongly upregulated GAX, suggesting that miR-221 downregulates a repressor of GAX. We next expressed miR-221 in ECs and identified ZEB2, a modulator of the epithelial-mesenchymal transition, as being strongly downregulated by miR-221. Using miR-221 expression constructs and an inhibitor, we determined that ZEB2 is upregulated by serum and downregulates GAX, while the expression of miR-221 upregulates GAX and downregulates ZEB2. A mutant miR-221 fails to downregulate ZEB2 or upregulate GAX. Finally, using chromatin immunoprecipitation, we identified two ZEB2 binding sites that modulate the ability of ZEB2 to downregulate GAX promoter activity. We conclude that miR-221 upregulates GAX primarily through its ability to downregulate the expression of ZEB2. These observations suggest a strategy for inhibiting angiogenesis by either recapitulating miR-221 expression or inhibiting ZEB2 activation. [ABSTRACT FROM AUTHOR]
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- 2010
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116. HIV1 Infection of FirstTrimester and Placental Tissue
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MAURY, WENDY, POTS, BARBARA J., and RABSON, ARNOLD B.
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- 1990
117. Inhibition of HIV-replication by a Tat RNA-binding domain peptide analog.
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Choudhury, Indrani, Wang, Jihong, Rabson, Arnold B., Stein, Steven, Pooyan, Shahriar, Stein, Stanley, and Leibowitz, Michael J.
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RNA-protein interactions , *HIV - Abstract
Presents a study on inhibition of HIV-1 replication by a Tat RNA-binding domain peptide analog. Methodology used to conduct study; Details on study conducted; Findings of study; Discussion on findings.
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- 1998
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118. Mesenchymal Stem Cells Use IDO to Regulate Immunity in Tumor Microenvironment.
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Weifang Ling, Jimin Zhang, Zengrong Yuan, Guangwen Ren, Liying Zhang, Xiaodong Chen, Rabson, Arnold B., Roberts, Arthur I., Ying Wang, and Yufang Shi
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MESENCHYMAL stem cells , *MULTIPOTENT stem cells , *INDOLEAMINE 2,3-dioxygenase , *MONOOXYGENASES , *TUMORS - Abstract
Mesenchymal stem cells (MSC) are present in most, if not all, tissues and are believed to contribute to tissue regeneration and the tissue immune microenvironment. Murine MSCs exert immunosuppressive effects through production of inducible nitric oxide synthase (iNOS), whereas human MSCs use indoleamine 2,3-dioxygenase (IDO). Thus, studies of MSC-mediated immunomodulation in mice may not be informative in the setting of human disease, although this critical difference has been mainly ignored. To address this issue, we established a novel humanized system to model human MSCs, using murine iNOS-/- MSCs that constitutively or inducibly express an ectopic human IDO gene. In this system, inducible IDO expression is driven by a mouse iNOS promoter that can be activated by inflammatory cytokine stimulation in a similar fashion as the human IDO promoter. These IDO-expressing humanized MSCs (MSC-IDO) were capable of suppressing T-lymphocyte proliferation in vitro. In melanoma and lymphoma tumor models, MSC-IDO promoted tumor growth in vivo, an effect that was reversed by the IDO inhibitor 1-methyl-tryptophan. We found that MSC-IDO dramatically reduced both tumor-infiltrating CD8+ Tcells andB cells. Our findings offer an important new line of evidence that interventional targeting of IDO activity could be used to restore tumor immunity in humans, by relieving IDO-mediated immune suppression of MSCs in the tumor microenvironment as well as in tumor cells themselves. [ABSTRACT FROM AUTHOR]
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- 2014
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119. Role of N F-κB in Regulation of PXR-mediated Gene Expression.
- Author
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Xinsheng Gu, Sui Ke, Duan Liu, Tao Sheng, Thomas, Paul E., Rabson, Arnold B., Gallo, Michael A., Wen Xie, and Yanan Tian
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GENE expression , *DNA , *GENETIC regulation , *CYTOKINES , *GLYCOPROTEINS , *MACROPHAGES , *TUMOR necrosis factors , *NUCLEOTIDE sequence - Abstract
It is a long-standing observation that inflammatory responses and infections decrease drug metabolism capacity in human and experimental animals. Cytochrome P-450 3A4 cyp304 is responsible for the metabolism of over 50% of current prescription drugs, and cyp3a4 expression is transcriptionally regulated by pregnane X receptor (PXR), which is a ligand-dependent transcription factor. In this study, we report that NF-κB activation by lipopolysaccharide and tumor necrosis factor-a plays a pivotal role in the suppression of cyp3a4 through interactions of NF-κB with the PXR-retinoid X receptor (RXR) complex. Inhibition of NF-κB by NF-κB-specific suppressor SRIκBα reversed the suppressive effects of lipopolysaccharide and tumor necrosis factor-α. Furthermore, we showed that NF-κB p65 disrupted the association of the PXR-RXRα complex with DNA sequences as determined by electrophoretic mobility shift assay and chromatin immunoprecipitation assays. NF-κB p65 directly interacted with the DNA-binding domain of RXRα and may prevent its binding to the consensus DNA sequences, thus inhibiting the transactivation by the PXR-RXRα complex. This mechanism of suppression by NF-κB activation may be extended to other nuclear receptor-regulated systems where RXRα is a dimerization partner. [ABSTRACT FROM AUTHOR]
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- 2006
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120. Dysregulated neuroimmune interactions and sustained type I interferon signaling after human immunodeficiency virus type 1 infection of human iPSC derived microglia and cerebral organoids.
- Author
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Boreland AJ, Stillitano AC, Lin HC, Abbo Y, Hart RP, Jiang P, Pang ZP, and Rabson AB
- Abstract
Human immunodeficiency virus type-1 (HIV-1) associated neurocognitive disorder (HAND) affects up to half of HIV-1 positive patients with long term neurological consequences, including dementia. There are no effective therapeutics for HAND because the pathophysiology of HIV-1 induced glial and neuronal functional deficits in humans remains enigmatic. To bridge this knowledge gap, we established a model simulating HIV-1 infection in the central nervous system using human induced pluripotent stem cell (iPSC) derived microglia combined with sliced neocortical organoids. Upon incubation with two replication-competent macrophage-tropic HIV-1 strains (JRFL and YU2), we observed that microglia not only became productively infected but also exhibited inflammatory activation. RNA sequencing revealed a significant and sustained activation of type I interferon signaling pathways. Incorporating microglia into sliced neocortical organoids extended the effects of aberrant type I interferon signaling in a human neural context. Collectively, our results illuminate the role of persistent type I interferon signaling in HIV-1 infected microglial in a human neural model, suggesting its potential significance in the pathogenesis of HAND., Competing Interests: COMPETING FINANCIAL INTERESTS The authors declare no competing financial interests.
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- 2023
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121. Effects of Wharton's jelly-derived mesenchymal stem cells on neonatal neutrophils.
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Khan I, Zhang L, Mohammed M, Archer FE, Abukharmah J, Yuan Z, Rizvi SS, Melek MG, Rabson AB, Shi Y, Weinberger B, and Vetrano AM
- Abstract
Background: Mesenchymal stem cells (MSCs) have been proposed as autologous therapy for inflammatory diseases in neonates. MSCs from umbilical cord Wharton's jelly (WJ-MSCs) are accessible, with high proliferative capacity. The effects of WJ-MSCs on neutrophil activity in neonates are not known. We compared the effects of WJ-MSCs on apoptosis and the expression of inflammatory, oxidant, and antioxidant mediators in adult and neonatal neutrophils., Methods: WJ-MSCs were isolated, and their purity and function were confirmed by flow cytometry. Neutrophils were isolated from cord and adult blood by density centrifugation. The effects of neutrophil/WJ-MSC co-culture on apoptosis and gene and protein expression were measured., Results: WJ-MSCs suppressed neutrophil apoptosis in a dose-dependent manner. WJ-MSCs decreased gene expression of NADPH oxidase-1 in both adult and neonatal neutrophils, but decreased heme oxygenase-1 and vascular endothelial growth factor and increased catalase and cyclooxygenase-2 in the presence of lipopolysaccharide only in adult cells. Similarly, generation of interleukin-8 was suppressed in adult but not neonatal neutrophils. Thus, WJ-MSCs dampened oxidative, vascular, and inflammatory activity by adult neutrophils, but neonatal neutrophils were less responsive. Conversely, Toll-like receptor-4, and cyclooxygenase-2 were upregulated in WJ-MSCs only in the presence of adult neutrophils, suggesting an inflammatory MSC phenotype that is not induced by neonatal neutrophils., Conclusion: Whereas WJ-MSCs altered gene expression in adult neutrophils in ways suggesting anti-inflammatory and antioxidant effects, these responses were attenuated in neonatal cells. In contrast, inflammatory gene expression in WJ-MSCs was increased in the presence of adult but not neonatal neutrophils. These effects should be considered in clinical trial design before WJ-MSC-based therapy is used in infants.
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- 2014
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122. 'Reduced malignancy as a mechanism for longevity in mice with adenylyl cyclase type 5 disruption'.
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De Lorenzo MS, Chen W, Baljinnyam E, Carlini MJ, La Perle K, Bishop SP, Wagner TE, Rabson AB, Vatner DE, Puricelli LI, and Vatner SF
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- Adenylyl Cyclase Inhibitors, Adenylyl Cyclases metabolism, Animals, Cell Proliferation drug effects, Enzyme Inhibitors pharmacology, Female, Mice, Mice, Knockout, Adenylyl Cyclases genetics, Gene Deletion, Longevity drug effects, Melanoma enzymology, Melanoma pathology
- Abstract
Disruption of adenylyl cyclase type 5 (AC5) knockout (KO) is a novel model for longevity. Because malignancy is a major cause of death and reduced lifespan in mice, the goal of this investigation was to examine the role of AC5KO in protecting against cancer. There have been numerous discoveries in genetically engineered mice over the past several decades, but few have been translated to the bedside. One major reason is that it is difficult to alter a gene in patients, but rather a pharmacological approach is more appropriate. The current investigation employs a parallel construction to examine the extent to which inhibiting AC5, either in a genetic knockout (KO) or by a specific pharmacological inhibitor protects against cancer. This study is unique, not only because a combined genetic and pharmacological approach is rare, but also there are no prior studies on the extent to which AC5 affects cancer. We found that AC5KO delayed age-related tumor incidence significantly, as well as protecting against mammary tumor development in AC5KO × MMTV-HER-2 neu mice, and B16F10 melanoma tumor growth, which can explain why AC5KO is a model of longevity. In addition, a Food and Drug Administration approved antiviral agent, adenine 9-β-D-arabinofuranoside (Vidarabine or AraAde), which specifically inhibits AC5, reduces LP07 lung and B16F10 melanoma tumor growth in syngeneic mice. Thus, inhibition of AC5 is a previously unreported mechanism for prevention of cancers associated with aging and that can be targeted by an available pharmacologic inhibitor, with potential consequent extension of lifespan., (© 2013 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)
- Published
- 2014
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123. PDCD2 controls hematopoietic stem cell differentiation during development.
- Author
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Kramer J, Granier CJ, Davis S, Piso K, Hand J, Rabson AB, and Sabaawy HE
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- Animals, Apoptosis, Apoptosis Regulatory Proteins genetics, Apoptosis Regulatory Proteins physiology, Core Binding Factor Alpha 2 Subunit genetics, Core Binding Factor Alpha 2 Subunit metabolism, Embryo, Nonmammalian blood supply, Embryo, Nonmammalian cytology, Embryo, Nonmammalian metabolism, Erythroid Cells metabolism, Erythropoiesis, Gene Expression, Gene Expression Regulation, Developmental, Gene Knockdown Techniques, Humans, Mice, Mitosis, Morpholinos genetics, Neovascularization, Physiologic, Organ Specificity, Transcription Factors genetics, Transcription Factors metabolism, Tumor Suppressor Protein p53 metabolism, Zebrafish, Zebrafish Proteins genetics, Zebrafish Proteins physiology, Apoptosis Regulatory Proteins metabolism, Cell Differentiation, Embryonic Development, Hematopoietic Stem Cells physiology, Zebrafish Proteins metabolism
- Abstract
Programmed cell death 2 (Pdcd2) is a highly conserved protein of undefined function, and is widely expressed in embryonic and adult tissues. The observations that knockout of Pdcd2 in the mouse is embryonic lethal at preimplantation stages, and that in Drosophila, Zfrp8, the ortholog of Pdcd2, is required for normal lymph gland development suggest that Pdcd2 is important for regulating hematopoietic development. Through genetic and functional studies, we investigated pdcd2 function during the zebrafish ontogeny. Knockdown of pdcd2 expression in zebrafish embryos resulted in defects in embryonic hematopoietic development. Loss of pdcd2 function caused increased expression of progenitor markers, and accumulation of erythroid progenitors during primitive hematopoiesis. Additionally, hematopoietic stem cells (HSCs) failed to appear in the aorta-gonad mesonephros, and were not able to terminally differentiate or reconstitute hematopoiesis. Pdcd2 effects on HSC emergence were cell autonomous and P53-independent, and loss of pdcd2 function was associated with mitotic defects and apoptosis. Restoration of runx1 function(s) and modulation of apoptosis through the inhibition of Jak/Stat signaling rescued the hematopoietic and erythroid defects resulting from pdcd2 knockdown. Our studies suggest that pdcd2 plays a critical role in regulating the transcriptional hierarchy controlling hematopoietic lineage determination. Furthermore, the effects of pdcd2 in regulating mitotic cell death may contribute to its role(s) in directing hematopoietic differentiation during development.
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- 2013
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124. Mesenchymal stromal cells protect mantle cell lymphoma cells from spontaneous and drug-induced apoptosis through secretion of B-cell activating factor and activation of the canonical and non-canonical nuclear factor κB pathways.
- Author
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Medina DJ, Goodell L, Glod J, Gélinas C, Rabson AB, and Strair RK
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- Animals, Antineoplastic Agents pharmacology, Apoptosis drug effects, Cell Communication, Cell Survival, Chemokine CXCL12 metabolism, Chemokine CXCL13 metabolism, Coculture Techniques, Drug Resistance, Neoplasm, Humans, Lymphoma, Mantle-Cell drug therapy, Mice, Stromal Cells physiology, B-Cell Activating Factor metabolism, Lymphoma, Mantle-Cell metabolism, Mesenchymal Stem Cells metabolism, NF-kappa B metabolism, Signal Transduction
- Abstract
Background: There is increasing evidence that stromal cell interactions are required for the survival and drug resistance of several types of B-cell malignancies. There is relatively little information regarding the role of the bone marrow/lymphoid microenvironment in the pathogenesis of mantle cell lymphoma. In this study we investigated the interaction of primary mantle cell lymphoma cells with stromal cells in an ex vivo co-culture system., Design and Methods: The murine stromal cell line MS-5 and human bone marrow mesenchymal stromal cells were each co-cultured with primary mantle cell lymphoma cells for up to 7 months. Mantle cell lymphoma cultures alone or combined with human stromal cells were analyzed for cell number, cell migration, nuclear factor-κB activation and drug resistance., Results: Co-culture of mantle cell lymphoma cells and human stromal cells results in the survival and proliferation of primary mantle cell lymphoma cells for at least 7 months compared to mantle cell lymphoma cells cultured alone. Mantle cell lymphoma-human stromal cell interactions resulted in activation of the B-cell activating factor/nuclear factor-κB signaling axis resulting in reduced apoptosis, increased mantle cell lymphoma migration and increased drug resistance., Conclusions: Direct mantle cell lymphoma-human stromal cell interactions support long-term expansion and increase the drug-resistance of primary mantle cell lymphoma cells. This is due in part to activation of the canonical and non-canonical nuclear factor κB pathways. We also demonstrated the ability of B-cell activating factor to augment CXCL12- and CXCL13-induced cell migration. Collectively, these findings demonstrate that human stromal cell-mantle cell lymphoma interactions play a pivotal role in the pathogenesis of mantle cell lymphoma and that analysis of mantle cell lymphoma-human stromal cell interactions may help in the identification of novel targets for therapeutic use.
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- 2012
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125. The tumor suppressor gene WWOX links the canonical and noncanonical NF-κB pathways in HTLV-I Tax-mediated tumorigenesis.
- Author
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Fu J, Qu Z, Yan P, Ishikawa C, Aqeilan RI, Rabson AB, and Xiao G
- Subjects
- Animals, Blotting, Western, Cell Proliferation, Cells, Cultured, Embryo, Mammalian cytology, Embryo, Mammalian metabolism, Female, Fibroblasts cytology, Fibroblasts metabolism, Flow Cytometry, Genes, Tumor Suppressor, HTLV-I Infections metabolism, HTLV-I Infections pathology, HTLV-I Infections virology, Human T-lymphotropic virus 1 genetics, Humans, I-kappa B Kinase genetics, I-kappa B Kinase metabolism, Immunoprecipitation, Jurkat Cells, Lymphoma, T-Cell metabolism, Lymphoma, T-Cell virology, Mice, Mice, Knockout, Mice, SCID, Mice, Transgenic, NF-kappa B genetics, NF-kappa B p52 Subunit, Oxidoreductases antagonists & inhibitors, Oxidoreductases genetics, Phosphorylation, RNA, Messenger genetics, RNA, Small Interfering genetics, Rats, Reverse Transcriptase Polymerase Chain Reaction, Transcription Factor RelA genetics, Transcription Factor RelA metabolism, Tumor Suppressor Proteins antagonists & inhibitors, Tumor Suppressor Proteins genetics, WW Domain-Containing Oxidoreductase, Cell Transformation, Neoplastic, Gene Products, tax physiology, Lymphoma, T-Cell pathology, NF-kappa B metabolism, Oxidoreductases metabolism, Signal Transduction, Tumor Suppressor Proteins metabolism
- Abstract
Both the canonical and noncanonical nuclear factor κB (NF-κB) pathways have been linked to tumorigenesis. However, it remains unknown whether and how the 2 signaling pathways cooperate during tumorigenesis. We report that inhibition of the noncanonical NF-κB pathway significantly delays tumorigenesis mediated by the viral oncoprotein Tax. One function of noncanonical NF-κB activation was to repress expression of the WWOX tumor suppressor gene. Notably, WWOX specifically inhibited Tax-induced activation of the canonical, but not the noncanonical NF-κB pathway. Mechanistic studies indicated that WWOX blocked Tax-induced inhibitors of κB kinaseα (IKKα) recruitment to RelA and subsequent RelA phosphorylation at S536. In contrast, WWOX Y33R, a mutant unable to block the IKKα recruitment and RelA phosphorylation, lost the ability to inhibit Tax-mediated tumorigenesis. These data provide one important mechanism by which Tax coordinates the 2 NF-κB pathways for tumorigenesis. These data also suggest a novel role of WWOX in NF-κB regulation and viral tumorigenesis.
- Published
- 2011
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126. Immune activation induces immortalization of HTLV-1 LTR-Tax transgenic CD4+ T cells.
- Author
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Swaims AY, Khani F, Zhang Y, Roberts AI, Devadas S, Shi Y, and Rabson AB
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- Animals, Apoptosis, CD4-Positive T-Lymphocytes cytology, CD4-Positive T-Lymphocytes metabolism, Cell Proliferation, Cytokines immunology, Gene Expression, Gene Products, tax genetics, Mice, Mice, Transgenic, T-Lymphocytes, Helper-Inducer immunology, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes pathology, Gene Products, tax immunology
- Abstract
Infection with the human T-cell leukemia virus-1 (HTLV-1) results in a variety of diseases including adult T-cell leukemia/lymphoma (ATL). Although the pathogenesis of these disorders is poorly understood, it involves complex interactions with the host immune system. Activation of infected T cells may play an important role in disease pathogenesis through induction of the oncogenic HTLV-1 Tax transactivator protein. To test this hypothesis, we employed transgenic mice in which Tax is regulated by the HTLV-1 LTR. T-cell receptor stimulation of LTR-Tax CD4(+) T cells induced Tax expression, hyper-proliferation, and immortalization in culture. The transition to cellular immortalization was accompanied by markedly increased expression of the antiapoptotic gene, mcl-1, previously implicated as important in T-cell survival. Immortalized cells exhibited a CD4(+)CD25(+)CD3(-) phenotype commonly observed in ATL. Engraftment of activated LTR-Tax CD4(+) T cells into NOD/Shi-scid/IL-2Rγ null mice resulted in a leukemia-like phenotype with expansion and tissue infiltration of Tax(+), CD4(+) lymphocytes. We suggest that immune activation of infected CD4(+) T cells plays an important role in the induction of Tax expression, T-cell proliferation, and pathogenesis of ATL in HTLV-1-infected individuals.
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- 2010
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127. MEOX2 regulates nuclear factor-kappaB activity in vascular endothelial cells through interactions with p65 and IkappaBbeta.
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Chen Y, Rabson AB, and Gorski DH
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- Animals, Binding Sites, Cells, Cultured, Gene Expression Regulation, Genes, Reporter, Homeodomain Proteins chemistry, Homeodomain Proteins genetics, Humans, Immunoprecipitation, Inhibitor of Differentiation Protein 1 genetics, Inhibitor of Differentiation Protein 1 metabolism, Inhibitor of Differentiation Proteins genetics, Inhibitor of Differentiation Proteins metabolism, Intercellular Adhesion Molecule-1 genetics, Intercellular Adhesion Molecule-1 metabolism, Interleukin-6 genetics, Interleukin-6 metabolism, Microscopy, Fluorescence, Muscle Proteins chemistry, Muscle Proteins genetics, Neoplasm Proteins genetics, Neoplasm Proteins metabolism, Promoter Regions, Genetic, Protein Interaction Domains and Motifs, Protein Interaction Mapping, Protein Structure, Tertiary, Rats, Transfection, Cell Nucleus metabolism, Endothelial Cells metabolism, Homeodomain Proteins metabolism, I-kappa B Kinase metabolism, Muscle Proteins metabolism, Transcription Factor RelA metabolism
- Abstract
Aims: Tumours secrete proangiogenic factors to induce the ingrowth of blood vessels, the end targets of which are vascular endothelial cells (ECs). The MEOX2 homeoprotein inhibits nuclear factor-kappaB (NF-kappaB) signalling and EC activation in response to serum and proangiogenic factors. We hypothesize that MEOX2 interacts with components of this pathway in vascular ECs to modulate NF-kappaB activity and EC activation and that these interactions depend upon specific domains within the MEOX2 protein., Methods and Results: To test our hypothesis, we transduced ECs with MEOX2 expression constructs. MEOX2 protein localized to the nuclear fraction, as did IkappaBbeta and p65. By co-immunoprecipitation, MEOX2 bound to both p65 and IkappaBbeta. Immunofluorescence demonstrated that MEOX2 colocalizes in the nucleus with both p65 and IkappaBbeta and that this colocalization requires the MEOX2 homeodomain and N-terminal domain. Finally, promoter assays revealed that MEOX2 expression has a biphasic effect on NF-kappaB-dependent promoters. At low levels, MEOX2 stimulates NF-kappaB activity, whereas at high levels, it represses, effects that also depend upon the homeodomain and the N-terminal domain., Conclusion: Our results represent the first report of an interaction between a homeobox protein and IkappaBbeta and suggest that MEOX2 modulates the activity of the RelA complex through direct interaction with its components. These observations implicate MEOX2 as a potentially important regulatory gene inhibiting not only the angiogenic response of ECs to proangiogenic factors, but also their response to chronic inflammatory stimulation that normally activates NF-kappaB, suggesting MEOX2 as a possible molecular target for the therapy of angiogenesis-dependent diseases such as cancer.
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- 2010
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128. Inhibition of NF-kappaB by (E)3-[(4-methylphenyl)-sulfonyl]-2-propenenitrile (BAY11-7082; BAY) is associated with enhanced 12-O-tetradecanoylphorbol-13-acetate-induced growth suppression and apoptosis in human prostate cancer PC-3 cells.
- Author
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Zheng X, Chang RL, Cui XX, Avila G, Huang MT, Liu Y, Kong AN, Rabson AB, and Conney AH
- Subjects
- Animals, Cell Proliferation drug effects, Humans, Male, Mice, Mice, Nude, Prostatic Neoplasms pathology, Apoptosis drug effects, NF-kappa B antagonists & inhibitors, Nitriles pharmacology, Prostatic Neoplasms drug therapy, Sulfones pharmacology, Tetradecanoylphorbol Acetate pharmacology
- Abstract
The effects of 12-O-tetradecanoylphorbol-13-acetate (TPA) alone or in combination with an NF-kappaB inhibitor, (E)3-[(4-methylphenyl)-sulfonyl]-2-propenenitrile (BAY 11-7082; BAY), on the growth and apoptosis of human prostate cancer PC-3 cells cultured in vitro or grown in immunodeficient mice were studied. Treatment of cultured PC-3 cells with TPA (0.2-10 ng/ml) for 96 h resulted in growth inhibition and apoptosis in a concentration-dependent manner. BAY inhibited NF-kappaB activity in PC-3 cells as determined by a luciferase reporter assay and enhanced TPA-induced growth inhibition and apoptosis in cultured PC-3 cells. In animal studies, NCr immunodeficient mice were injected subcutaneously with PC-3 cells in Matrigel. Mice with well-established tumors received daily i.p. injections with TPA (100 ng/g body weight/day), BAY (4 microg/g/day), or a combination of TPA (100 ng/g/day) and BAY (4 microg/g/day) for 36 days. Tumor growth occurred in all of the vehicle-treated control mice. The percent of animals with some tumor regression after 36 days of treatment was 0% for the control group, 40% for the TPA group, 50% for the BAY group and 100% for the TPA + BAY group. Mechanistic studies indicated that treatment of the mice with TPA or TPA + BAY decreased proliferation and increased apoptosis in the tumors. Results from our studies indicate that inhibition of NF-kappaB activity is associated with enhanced TPA-induced growth inhibition and apoptosis in PC-3 cells. Inhibition of NF-kappaB activity by suitable pharmacological inhibitors may be an effective strategy for improving the therapeutic efficacy of TPA in prostate cancer.
- Published
- 2008
129. Curcumin downregulates the constitutive activity of NF-kappaB and induces apoptosis in novel mouse melanoma cells.
- Author
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Marín YE, Wall BA, Wang S, Namkoong J, Martino JJ, Suh J, Lee HJ, Rabson AB, Yang CS, Chen S, and Ryu JH
- Subjects
- Animals, Annexin A5 metabolism, Caspase 3 metabolism, Cell Proliferation drug effects, Cell Survival drug effects, Cyclin D, Cyclins genetics, Cyclins metabolism, Cyclooxygenase 2, Down-Regulation, Electrophoretic Mobility Shift Assay, G1 Phase drug effects, Luciferases metabolism, Melanoma, Experimental metabolism, Mice, Skin Neoplasms drug therapy, Skin Neoplasms metabolism, Skin Neoplasms pathology, Tumor Cells, Cultured, Antineoplastic Agents pharmacology, Apoptosis drug effects, Curcumin pharmacology, Melanoma, Experimental pathology, NF-kappa B metabolism
- Abstract
Melanoma, the most deadly form of skin cancer, is very aggressive and resistant to present therapies. The transcription factor nuclear factor-kappa B (NF-kappaB) has been reported to be constitutively active in many types of cancer. Constitutively active NF-kappaB seen in melanoma likely plays a central role in cell survival and growth. We have established and characterized novel cell lines from our murine melanoma model. Here we report the constitutive activity of NF-kappaB in these melanoma-derived cells, as shown by electrophoretic mobility shift assay and reporter assays. We hypothesized that agents that inhibit NF-kappaB may also inhibit cell proliferation and may induce apoptosis in such melanoma cells. Curcumin has been shown to inhibit NF-kappaB activity in several cell types. In our system, curcumin selectively inhibited growth of melanoma cells, but not normal melanocytes. Curcumin induced melanoma cells to undergo apoptosis, as shown by caspase-3 activation, inversion of membrane phosphatidyl serine, and increases in cells in the sub-G1 phase. A curcumin dose-dependent inhibition of NF-kappaB-driven reporter activity correlated with decreased levels of phospho-IkappaBalpha, and decreased expression of NF-kappaB-target genes COX-2 and cyclin D1. This study demonstrates that the use of cells from our model system can facilitate studies of signaling pathways in melanoma. We furthermore conclude that curcumin, a natural and safe compound, inhibits NF-kappaB activity and the expression of its downstream target genes, and also selectively induces apoptosis of melanoma cells but not normal melanocytes. These encouraging in-vitro results support further investigation of curcumin for treatment of melanoma in vivo.
- Published
- 2007
- Full Text
- View/download PDF
130. Role of NF-kappaB in regulation of PXR-mediated gene expression: a mechanism for the suppression of cytochrome P-450 3A4 by proinflammatory agents.
- Author
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Gu X, Ke S, Liu D, Sheng T, Thomas PE, Rabson AB, Gallo MA, Xie W, and Tian Y
- Subjects
- Cytochrome P-450 CYP3A, Dimerization, Down-Regulation immunology, Electrophoretic Mobility Shift Assay, Gene Expression Regulation immunology, Humans, Inactivation, Metabolic physiology, Pregnane X Receptor, Receptors, Cytoplasmic and Nuclear chemistry, Receptors, Steroid chemistry, Retinoid X Receptor alpha chemistry, Retinoid X Receptor alpha metabolism, Transcriptional Activation physiology, Cytochrome P-450 Enzyme System genetics, Inflammation physiopathology, Lipopolysaccharides pharmacology, Receptors, Cytoplasmic and Nuclear metabolism, Receptors, Steroid metabolism, Transcription Factor RelA metabolism, Tumor Necrosis Factor-alpha pharmacology
- Abstract
It is a long-standing observation that inflammatory responses and infections decrease drug metabolism capacity in human and experimental animals. Cytochrome P-450 3A4 cyp304 is responsible for the metabolism of over 50% of current prescription drugs, and cyp3a4 expression is transcriptionally regulated by pregnane X receptor (PXR), which is a ligand-dependent transcription factor. In this study, we report that NF-kappaB activation by lipopolysaccharide and tumor necrosis factor-alpha plays a pivotal role in the suppression of cyp3a4 through interactions of NF-kappaB with the PXR.retinoid X receptor (RXR) complex. Inhibition of NF-kappaB by NF-kappaB-specific suppressor SRIkappaBalpha reversed the suppressive effects of lipopolysaccharide and tumor necrosis factor-alpha. Furthermore, we showed that NF-kappaB p65 disrupted the association of the PXR.RXRalpha complex with DNA sequences as determined by electrophoretic mobility shift assay and chromatin immunoprecipitation assays. NF-kappaB p65 directly interacted with the DNA-binding domain of RXRalpha and may prevent its binding to the consensus DNA sequences, thus inhibiting the transactivation by the PXR.RXRalpha complex. This mechanism of suppression by NF-kappaB activation may be extended to other nuclear receptor-regulated systems where RXRalpha is a dimerization partner.
- Published
- 2006
- Full Text
- View/download PDF
131. Enhancement of TPA-induced growth inhibition and apoptosis in myeloid leukemia cells by BAY 11-7082, an NF-kappaB inhibitor.
- Author
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Hansson A, Marín YE, Suh J, Rabson AB, Chen S, Huberman E, Chang RL, Conney AH, and Zheng X
- Subjects
- Active Transport, Cell Nucleus, Cell Adhesion, Cell Differentiation, Cell Line, Tumor, Cell Nucleus metabolism, Cell Survival, DNA chemistry, DNA Damage, Dose-Response Relationship, Drug, HL-60 Cells, Humans, I-kappa B Proteins metabolism, Immunophenotyping, NF-KappaB Inhibitor alpha, NF-kappa B metabolism, Phosphorylation, Propidium pharmacology, Protein Kinase C metabolism, Protein Kinase C beta, Time Factors, Apoptosis, Cell Proliferation drug effects, Drug Resistance, Neoplasm, Gene Expression Regulation, Neoplastic, Leukemia, Myeloid drug therapy, NF-kappa B antagonists & inhibitors, Nitriles pharmacology, Sulfones pharmacology, Tetradecanoylphorbol Acetate pharmacology
- Abstract
The phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA) is a potent stimulator of differentiation and apoptosis in myeloid leukemia cells. In the present study, we investigated the role of the transcription factor NF-kappaB in TPA-induced growth inhibition and apoptosis in the myeloid leukemia HL-60 cell line and its TPA-resistant cell variant HL-525. Unlike the parental cell line, HL-525 cells are protein kinase C (PKC)-beta deficient and resistant to TPA-induced differentiation and apoptosis. We found that treatment of HL-60 cells with TPA resulted in a concentration-dependent growth inhibition and an increase in apoptotic cells. TPA only had a small effect on growth and apoptosis in HL-525 cells. Treatment of HL-60 cells with TPA (0.64-3.2 nM) caused a rapid activation of NF-kappaB as determined by electrophoresis mobility shift assay (EMSA) and immunocytochemistry. Although the basal level of NF-kappaB activity was low in HL-60 cells, TPA-resistant HL-525 cells had a high basal level of NF-kappaB activity. Treatment of HL-525 cells with higher concentrations of TPA (16-80 nM) resulted in a further increase in NF-kappaB activity. (E)3-[(4-methylphenyl)-sulfonyl]-2-propenenitrile (BAY 11-7082; BAY), which inhibits IkappaB alpha phosphorylation and thus decreases NF-kappaB activation, was found to decrease TPA-induced nuclear translocation of NF-kappaB. Furthermore, BAY enhanced TPA-induced growth inhibition and apoptosis in both HL-60 and HL-525 cells. Results from the present study indicate that inhibition of NF-kappaB by BAY was associated with enhanced TPA-induced growth inhibition and apoptosis in human myeloid leukemia cells. TPA in combination with pharmacological inhibitors of NF-kappaB may improve the therapeutic efficacy of TPA and overcome the resistance to TPA in some myeloid leukemia patients.
- Published
- 2005
132. From microarray to bedside: targeting NF-kappaB for therapy of lymphomas.
- Author
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Rabson AB and Weissmann D
- Subjects
- Animals, Apoptosis, Humans, Lymphoma, B-Cell metabolism, Lymphoma, Large B-Cell, Diffuse metabolism, Models, Biological, Neoplasms metabolism, Prognosis, Gene Expression Regulation, Developmental, Lymphoma therapy, Lymphoma, B-Cell therapy, Lymphoma, Large B-Cell, Diffuse therapy, NF-kappa B metabolism, Oligonucleotide Array Sequence Analysis methods, Signal Transduction
- Published
- 2005
133. NF-kappaB activation in human prostate cancer: important mediator or epiphenomenon?
- Author
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Suh J and Rabson AB
- Subjects
- Cyclin D1 metabolism, Genes, myc physiology, Humans, Male, Metalloendopeptidases metabolism, NF-kappa B genetics, Prostatic Neoplasms genetics, Cell Division physiology, Gene Expression Regulation, Neoplastic physiology, NF-kappa B metabolism, Prostatic Neoplasms metabolism, Receptors, Androgen metabolism
- Abstract
The NF-kappaB family of transcription factors has been shown to be constitutively activated in various human malignancies, including leukemias, lymphomas, and a number of solid tumors. NF-kappaB is hypothesized to contribute to development and/or progression of malignancy by regulating the expression of genes involved in cell growth and proliferation, anti-apoptosis, angiogenesis, and metastasis. Prostate cancer cells have been reported to have constitutive NF-kappaB activity due to increased activity of the IkappaB kinase complex. Furthermore, an inverse correlation between androgen receptor (AR) status and NF-kappaB activity was observed in prostate cancer cell lines. NF-kappaB may promote cell growth and proliferation in prostate cancer cells by regulating expression of genes such as c-myc, cyclin D1, and IL-6. NF-kappaB may also inhibit apoptosis in prostate cancer cells through activation of expression of anti-apoptotic genes, such as Bcl-2, although pro-apoptotic activity of NF-kappaB has also been reported. NF-kappaB-mediated expression of genes involved in angiogenesis (IL-8, VEGF), and invasion and metastasis (MMP9, uPA, uPA receptor) may further contribute to the progression of prostate cancer. Constitutive NF-kappaB activity has also been demonstrated in primary prostate cancer tissue samples and suggested to have prognostic importance for a subset of primary tumors. The limited number of samples analyzed in those studies and the relative lack of NF-kappaB target genes identified in RNA expression microarray analyses of prostate cancer cells suggest that further studies will be required in order to determine if NF-kappaB actually plays a role in human prostate cancer development, and/or progression, and to characterize its potential as a therapeutic target., (Copyright 2003 Wiley-Liss, Inc.)
- Published
- 2004
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134. Fratricidal retroviruses: a new twist in gene therapy.
- Author
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Rabson AB
- Subjects
- Animals, Antiviral Agents pharmacology, Cells, Cultured, Gene Expression Regulation, Viral, Genetic Therapy, Genetic Vectors, Humans, Prodrugs, Retroviridae Infections genetics, Retroviridae Proteins, Oncogenic metabolism, Transgenes, Tumor Virus Infections genetics, Viral Envelope Proteins metabolism, Leukemia Virus, Feline physiology, Retroviridae Infections therapy, Retroviridae Proteins, Oncogenic genetics, Tumor Virus Infections therapy, Viral Envelope Proteins genetics, Virus Diseases therapy, Virus Replication
- Published
- 2003
- Full Text
- View/download PDF
135. Ah receptor and NF-kappaB interactions: mechanisms and physiological implications.
- Author
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Tian Y, Rabson AB, and Gallo MA
- Subjects
- Animals, Gene Expression Regulation drug effects, Humans, Immune Tolerance drug effects, NF-kappa B metabolism, Polychlorinated Dibenzodioxins pharmacology, Receptors, Aryl Hydrocarbon metabolism
- Abstract
The aryl hydrocarbon (Ah) receptor mediates most of the toxic effects induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds, which are ubiquitous environmental contaminants causing toxic responses in human and wildlife. Nuclear factor kappa B (NF-kappaB) is a pleiotropic transcription factor that plays a pivotal role in a wide array of physiological and pathological responses including immune modulation, inflammatory responses and apoptosis. Many physiological functions adversely affected by TCDD are also known to be regulated by NF-kappaB, such as immune activation, maintenance of skin differentiation, control of cell proliferation and survival, as well as induction of xenobiotic metabolizing enzymes. In the past few years, evidence has emerged to show that the Ah receptor and NF-kappaB interact and transcriptionally modulate each other. This review discusses Ah receptor-NF-kappaB interactions and examines potential mechanistic explanations for toxic responses as a result of TCDD exposure and the suppression of cytochrome P450 1A1/1A2 by stress stimuli such as inflammation and infection.
- Published
- 2002
- Full Text
- View/download PDF
136. Mechanisms of constitutive NF-kappaB activation in human prostate cancer cells.
- Author
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Suh J, Payvandi F, Edelstein LC, Amenta PS, Zong WX, Gélinas C, and Rabson AB
- Subjects
- DNA-Binding Proteins metabolism, Humans, I-kappa B Kinase, Male, NF-KappaB Inhibitor alpha, Prostatic Neoplasms pathology, Protein Serine-Threonine Kinases metabolism, Protein-Tyrosine Kinases metabolism, Tumor Cells, Cultured, NF-kappaB-Inducing Kinase, I-kappa B Proteins, NF-kappa B physiology, Prostatic Neoplasms metabolism
- Abstract
Background: Activation of the NF-kappaB transcription factor has been previously demonstrated in two androgen receptor negative prostate cancer cell lines. We wished to extend this work to additional prostate cancer cells and to characterize the mechanisms responsible for constitutive NF-kappaB activation., Methods: Electrophoretic mobility shift assays were performed to measure NF-kappaB DNA-binding activity in prostate cancer cell lines, and immunohistochemistry was performed to detect nuclear localization of NF-kappaB in prostate cancer tissues. Western blot analysis was used to study the status of IkappaBalpha. Transient transfection assays were employed to characterize the contributions of IkappaB kinase (IKK), MAPK kinase kinases (MAPKKKs), androgen receptor (AR), and tyrosine phosphorylation to the constitutive activation of NF-kappaB in the prostate cancer cell lines., Results: Constitutive NF-kappaB activity was observed in AR-negative cell lines as well as in the prostate cancer patient samples, but was not present in AR positive cells. A "super-repressor" IkappaBalpha, as well as dominant negative forms of IKKbeta and NF-kappaB-inducing kinase (NIK), and tyrosine kinase inhibition were able to suppress NF-kappaB activity in the cells with constitutive activation., Conclusions: The constitutive activation of NF-kappaB observed in prostate cancer cells is likely due to a signal transduction pathway involving tyrosine kinases, NIK, and IKK activation., (Copyright 2002 Wiley-Liss, Inc.)
- Published
- 2002
- Full Text
- View/download PDF
137. Administration of a phorbol ester to patients with hematological malignancies: preliminary results from a phase I clinical trial of 12-O-tetradecanoylphorbol-13-acetate.
- Author
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Strair RK, Schaar D, Goodell L, Aisner J, Chin KV, Eid J, Senzon R, Cui XX, Han ZT, Knox B, Rabson AB, Chang R, and Conney A
- Subjects
- Adult, Aged, Cells, Cultured, DNA, Complementary metabolism, Female, HL-60 Cells, Hematologic Neoplasms metabolism, Humans, Immunophenotyping, Male, Middle Aged, Oligonucleotide Array Sequence Analysis, Phenotype, Tetradecanoylphorbol Acetate pharmacology, Time Factors, Hematologic Neoplasms drug therapy, Tetradecanoylphorbol Acetate therapeutic use
- Abstract
Purpose: Phorbol esters are capable of inducing a broad range of cellular effects,including the maturation/differentiation of hematopoietic cell lines (E. Huberman and M. F. Callaham, Proc. Natl. Acad. Sci. USA, 76: 1293-1297, 1979; J. Lotem and L. Sachs, Proc. Natl. Acad. Sci. USA, 76: 5158-5162, 1979; G. Rovera et al., Proc. Natl. Acad. Sci. USA, 76: 2779-2783, 1979; H. P. Koeffler, J. Clin. Investig., 66: 1101-1108, 1980). The ability to induce this differentiation at very low concentrations stimulated investigators to administer a phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA), to patients with myeloid leukemias in the People's Republic of China (Z. T. Han et al., Proc. Natl. Acad. Sci. USA, 95: 5357-5361, 1998). The tolerability of this therapy in China prompted Phase I studies of TPA in the United States. The purpose of this report is to demonstrate the tolerance of TPA at doses that result in detectable biological activity in blood and malignant cells., Experimental Design: TPA was administered to patients with relapsed/refractory hematological malignancies., Results: Phenotypic effects were detected in malignant cells and TPA-associated biological activity was present in blood for up to several hours after the infusion., Conclusions: These studies confirm the feasibility of TPA administration to humans and establish the foundation for the development of phorbol esters as therapy for patients with a variety of malignant and nonmalignant disorders.
- Published
- 2002
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