Showing papers by "David E. Levy published in 2012"
TL;DR: Evidence for a yin-yang of IFN function through its role in modulating crosstalk between multiple cytokines by both feedforward and feedback regulation of common signaling intermediates is reviewed and a homeostatic role for IFN through tonic signaling in the absence of acute infection is postulated.
389 citations
TL;DR: In mice, it is shown that effector T cells cannot accumulate within the decidua, the specialized stromal tissue encapsulating the fetus and placenta, and this findings give insight into mechanisms of fetomaternal immune tolerance, as well as reveal the epigenetic modification of tissueStromal cells as a modality for limitingEffector T cell trafficking.
Abstract: The chemokine-mediated recruitment of effector T cells to sites of inflammation is a central feature of the immune response. The extent to which chemokine expression levels are limited by the intrinsic developmental characteristics of a tissue has remained unexplored. We show in mice that effector T cells cannot accumulate within the decidua, the specialized stromal tissue encapsulating the fetus and placenta. Impaired accumulation was in part attributable to the epigenetic silencing of key T cell–attracting inflammatory chemokine genes in decidual stromal cells, as evidenced by promoter accrual of repressive histone marks. These findings give insight into mechanisms of fetomaternal immune tolerance, as well as reveal the epigenetic modification of tissue stromal cells as a modality for limiting effector T cell trafficking.
352 citations
TL;DR: Spontaneous mammary tumors that develop in STAT1-/- mice closely recapitulate the progression, ovarian hormone responsiveness, and molecular characteristics of human luminal breast cancer, the most common subtype of human breast neoplasms, and thus represent a valuable platform for testing novel treatments and detection modalities.
Abstract: Although breast cancers expressing estrogen receptor-α (ERα) and progesterone receptors (PR) are the most common form of mammary malignancy in humans, it has been difficult to develop a suitable mouse model showing similar steroid hormone responsiveness. STAT transcription factors play critical roles in mammary gland tumorigenesis, but the precise role of STAT1 remains unclear. Herein, we show that a subset of human breast cancers display reduced STAT1 expression and that mice lacking STAT1 surprisingly develop ERα+/PR+ mammary tumors. We used a combination of approaches, including histological examination, gene targeted mice, gene expression analysis, tumor transplantaion, and immunophenotyping, to pursue this study. Forty-five percent (37/83) of human ERα+ and 22% (17/78) of ERα- breast cancers display undetectable or low levels of STAT1 expression in neoplastic cells. In contrast, STAT1 expression is elevated in epithelial cells of normal breast tissues adjacent to the malignant lesions, suggesting that STAT1 is selectively downregulated in the tumor cells during tumor progression. Interestingly, the expression levels of STAT1 in the tumor-infiltrating stromal cells remain elevated, indicating that single-cell resolution analysis of STAT1 level in primary breast cancer biopsies is necessary for accurate assessment. Female mice lacking functional STAT1 spontaneously develop mammary adenocarcinomas that comprise > 90% ERα+/PR+ tumor cells, and depend on estrogen for tumor engraftment and progression. Phenotypic marker analyses demonstrate that STAT1-/- mammary tumors arise from luminal epithelial cells, but not myoepithelial cells. In addition, the molecular signature of the STAT1-/- mammary tumors overlaps closely to that of human luminal breast cancers. Finally, introduction of wildtype STAT1, but not a STAT1 mutant lacking the critical Tyr701 residue, into STAT1-/- mammary tumor cells results in apoptosis, demonstrating that the tumor suppressor function of STAT1 is cell-autonomous and requires its transcriptional activity. Our findings demonstrate that STAT1 suppresses mammary tumor formation and its expression is frequently lost during breast cancer progression. Spontaneous mammary tumors that develop in STAT1-/- mice closely recapitulate the progression, ovarian hormone responsiveness, and molecular characteristics of human luminal breast cancer, the most common subtype of human breast neoplasms, and thus represent a valuable platform for testing novel treatments and detection modalities.
157 citations
TL;DR: Altering pyrimidine levels in influenza virus– or VSV-infected cells reverses the inhibitory effect of viral proteins NS1 and M on host mRNA nuclear export, restoring expression of host antiviral factors.
Abstract: The NS1 protein of influenza virus is a major virulence factor essential for virus replication, as it redirects the host cell to promote viral protein expression. NS1 inhibits cellular messenger ribonucleic acid (mRNA) processing and export, down-regulating host gene expression and enhancing viral gene expression. We report in this paper the identification of a nontoxic quinoline carboxylic acid that reverts the inhibition of mRNA nuclear export by NS1, in the absence or presence of the virus. This quinoline carboxylic acid directly inhibited dihydroorotate dehydrogenase (DHODH), a host enzyme required for de novo pyrimidine biosynthesis, and partially reduced pyrimidine levels. This effect induced NXF1 expression, which promoted mRNA nuclear export in the presence of NS1. The release of NS1-mediated mRNA export block by DHODH inhibition also occurred in the presence of vesicular stomatitis virus M (matrix) protein, another viral inhibitor of mRNA export. This reversal of mRNA export block allowed expression of antiviral factors. Thus, pyrimidines play a necessary role in the inhibition of mRNA nuclear export by virulence factors.
55 citations
01 Jan 2012
TL;DR: Comparative genomics analyses indicate that whole genome duplications and gene duplications by unequal chromosomal crossing over were likely the major mechanisms underlying the evolution of STATs.
Abstract: The STAT signaling pathway is one of the seven common pathways that govern cell fate decisions during animal development. Comparative genomics revealed multiple incidences of stat gene duplications throughout metazoan evolutionary history. While pseudogenization is a frequent fate of duplicated genes, many of these STAT duplications evolved into novel genes through rapid sequence diversification and neofunctionalization. Additionally, the core of STAT gene regulatory networks, comprising stat1 through 4, stat5 and stat6, arose early in vertebrate evolution, probably through the two whole genome duplication events that occurred after the split of Cephalochordates but before the rise of Chondrichthyes. While another complete genome duplication event took place during the evolution of bony fish after their separation from the tetrapods about 450 million years ago (Mya), modern fish have only one set of these core stats, suggesting the rapid loss of most duplicated stat genes. The two stat5 genes in mammals likely arose from a duplication event in early Eutherian evolution, a period from about 310 Mya at the avian-mammal divergence to the separation of marsupials from other mammals about 130 Mya. These analyses indicate that whole genome duplications and gene duplications by unequal chromosomal crossing over were likely the major mechanisms underlying the evolution of STATs.
52 citations
TL;DR: Evidence is provided of a STAT-family protein regulating the structure of a cytoplasmic organelle and implicate this mechanism in the pathogenesis of a human disease.
Abstract: We report unexpected nongenomic functions of signal transducer and activator of transcription (STAT) 5 species in the cytoplasm aimed at preserving the structure and function of the Golgi apparatus...
50 citations
TL;DR: It is shown that the Irf7 gene is regulated by transcription factors STAT1 and IRF9 in response to the type II interferon (IFN) IFN-γ, and a biologically relevant basal activity of TBK1 is described to identify IRF7 as a novel player in the IFn-γ response.
Abstract: Signal transducers and activators of transcription (STATs) and interferon regulatory factors (IRFs) share common target genes. Here we show that the Irf7 gene is regulated by transcription factors STAT1 and IRF9 in response to the type II interferon (IFN) IFN-γ. IRF7 cooperated with STAT1 and IRF1 to stimulate the expression of a subset of IFN-γ-induced STAT1 target genes. IRF7-mediated control of the Gbp2 gene required the presence and basal activity of the S/T kinase TANK-binding kinase 1 (TBK1), whereas the binding of IRF7 to the Gbp2 promoter did not. Analysis of RNA polymerase II (Pol II) recruitment to the Gbp2 promoter revealed a role for IRF7 at later stages of the IFN-γ response. In support of the role of IRF7 in establishing an effective antibacterial response, IFN-γ-pretreated Irf7−/− macrophages showed an increased bacterial burden after infection with Listeria monocytogenes. Our data thus describe a biologically relevant basal activity of TBK1 and identify IRF7 as a novel player in the IFN-γ response.
33 citations
TL;DR: Examining tetramer function in vivo and showing that STAT5 tetramers function primarily as transcriptional activators is shown.
12 citations
01 Jan 2012
TL;DR: Nongenomic functions of STAT3 include action in the cell cytoplasm and in mitochondria, where it impacts metabolic activities involved in a diverse set of cell functions, including malignant transformation.
Abstract: STAT3 was discovered as a transcription factor activated during inflammatory cytokine signaling, largely through the action of cytokines that utilize receptors that engage the gp130 signal transducer. While the paradigm of receptor-dependent protein tyrosine phosphorylation of STAT3 has explained many of the biological activities ascribed to this protein, additional functions have been discovered in recent years. These functions involve actions of STAT3 outside the nucleus and do not rely on its ability to interact with chromatin and trigger gene expression. Nongenomic functions of STAT3 include action in the cell cytoplasm and in mitochondria, where it impacts metabolic activities involved in a diverse set of cell functions, including malignant transformation.
10 citations