James E. Darnell's research while affiliated with The Rockefeller University and other places
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Publications (179)
The discovery of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway arose from investigations of how cells respond to interferons (IFNs), revealing a paradigm in cell signaling conserved from slime molds to mammals. These discoveries revealed mechanisms underlying rapid gene expression mediated by a wide variety...
By using a cell fraction technique that separates chromatin associated nascent RNA, newly completed nucleoplasmic mRNA and cytoplasmic mRNA, we have shown that residues in exons are methylated (m6A) in nascent pre-mRNA and remain methylated in the same exonic residues in nucleoplasmic and cytoplasmic mRNA. Thus, there is no evidence of a substantia...
Understanding the biologic role of N⁶-methyladenosine (m⁶A) RNA modifications in mRNA requires an understanding of when and where in the life of a pre-mRNA transcript the modifications are made. We found that HeLa cell chromatin-associated nascent pre-mRNA (CA-RNA) contains many unspliced introns and m⁶A in exons but very rarely in introns. The m⁶A...
Significance
Examination of mutants in linker domain of STAT3 suggests contacts with both the DNA binding and SH2 domains that may cause structural changes and affect pSTAT3-dependent transcription, opening the possibility of new targets for drug inhibition of pSTAT3.
We adapted UV CLIP (cross-linking immunoprecipitation) to accurately locate tens of thousands of m(6)A residues in mammalian mRNA with single-nucleotide resolution. More than 70% of these residues are present in the 3'-most (last) exons, with a very sharp rise (sixfold) within 150-400 nucleotides of the start of the last exon. Two-thirds of last ex...
In this Reflections, I review a few early and very lucky events that gave me a running start for the rest of a long and wonderfully
enjoyable career. For the main part, a discussion is provided of what I recall as the main illuminating results that my many
dozens of students and postdoctoral fellows (approximately 140 in all) provided to our bioche...
Several strong conclusions emerge concerning pre-mRNA processing from both old and newer experiments. The RNAPII complex is involved with pre-mRNA processing through binding of processing proteins to the CTD (carboxyl terminal domain) of the largest RNAPII subunit. These interactions are necessary for efficient processing, but whether factor bindin...
We look back on the discoveries that the tyrosine kinases TYK2 and JAK1 and the transcription factors STAT1, STAT2, and IRF9 are required for the cellular response to type I interferons. This initial description of the JAK-STAT pathway led quickly to additional discoveries that type II interferons and many other cytokines signal through similar mec...
Oncogenes as the center of cancer research focused attention 30 years ago on signal transduction especially tyrosine phosphorylation. Discovery that the Jun oncoprotein was a site-specific DNA binding protein demanded a connection of signaling abnormalities with transcriptional control [1]. The cytokine responsive Jak-STAT pathway, discovered throu...
Inspiration and innovation in molecular cancer research.
Persistently activated STAT3 contributes to cell survival in many different human cancers. Cancer cell secretion of IL-6 is a frequent basis for persistent STAT3 activation; we show that antibodies against IL-6 or gp-130, the signaling unit of the IL-6 receptor, can abruptly remove persistently activated STAT3 causing prompt disappearance of cystei...
The proapoptotic factors Reaper, Hid, Grim, and Sickle regulate apoptosis in Drosophila by inhibiting the antiapoptotic factor DIAP1 (Drosophila inhibitor of apoptosis 1). Heat, UV light, x-rays, and developmental signals can all increase the proapoptotic factors, but the control of transcription of the diap1 gene is unclear. We show that in imagin...
Cooperation between STAT3 and c-Jun in driving transcription during transfection of reporter constructs is well established,
and both proteins are present on some interleukin-6 (IL-6) STAT3-dependent promoters on chromosomal loci. We report that small
interfering RNA knockdown of c-Jun or c-Fos diminishes IL-6 induction of some but not all STAT3-de...
Celebrations are certainly in order for the 50th anniversary of the Isaacs/Lindenmann discovery of interferon as a secreted substance of probable cellular origin that conferred resistance to at least four viruses of distinctly different character--influenza, Sendai, Newcastle's disease, and vaccinia. Personal pride, excusable, I hope, leads me to r...
We report experiments that infer a radical reorientation of tyrosine-phosphorylated parallel STAT1 dimers to an antiparallel form. Such a change in structure allows easy access to a phosphatase. With differentially epitope-tagged molecules, we show that the two monomers of a dimer remain together during dephosphorylation although they most likely u...
Dysregulation of the JAK-STAT pathway is implicated in human cancer and leads to a hematopoietic tumor phenotype in flies. Now, an enhancer-suppressor screen of the fly tumor model connects the JAK kinase Hopscotch pathway with chromatin-modifying proteins and heterochromatic gene silencing.
Signal transducers and activators of transcription 3 (STAT3) is a transcription factor that is aberrantly activated in many cancer cells. Constitutively activated STAT3 is oncogenic, presumably as a consequence of the genes that it differentially regulates. Activated STAT3 correlated with elevated cyclin D1 protein in primary breast tumors and brea...
The transcription factor STAT3 is overactive in many tumors and has attracted attention as a drug target. But in vivo evidence suggesting that inhibiting STAT3 could counteract cancer has been incomplete. The picture in the whole animal now begins to clarify, and it bodes well for this approach ( pages 623 - 629).
Phosphorylation on Y705 is obligatory for STAT3 activation, but full transcriptional activity of this widely expressed protein also requires phosphorylation on S727. We described earlier the STAT3 SA/- mice (SA, S727A allele) on a Black 6 (Bl6) background that showed 75% perinatal lethality and early growth retardation presumably due to the decreas...
The crystal structure has been determined at 3.0 A resolution for an unphosphorylated STAT1 (1-683) complexed with a phosphopeptide derived from the alpha chain of interferon gamma (IFNgamma) receptor. Two dimer interfaces are seen, one between the N domains (NDs) (amino acid residues 1-123) and the other between the core fragments (CFs) (residues...
IFN-γ treatment of cells leads to tyrosine phosphorylation of signal transducer and activator of transcription (STAT) 1 followed by dimerization through a reciprocal Src homology 2–phosphotyrosine interaction near the –COOH end of each monomer, forming a parallel structure that accumulates in the nucleus to drive transcription. Prompt dephosphoryla...
Induced transformation of mouse fibroblasts was carried out by releasing tetracycline-repressed expression of an oncogenic mutant of STAT3, STAT3-C, or of v-Src or Ha-Ras. At 15 days after derepression of each oncogene, DNA microarrays showed elevation (>3-fold) of a similar group of approximately 25 mRNAs compared to untransformed cells. RT-PCR co...
We describe a detailed time course of the assembly and disassembly of a STAT3-dependent, glucocorticoid-supplemented enhanceosome for the alpha2-macroglobulin (alpha2-M) gene and compare this with a detailed time course of transcription of the gene by run-on analysis. The glucocorticoid receptor (GR) can associate with the enhanceosome without STAT...
Interferon-induced transcription depends upon tyrosine phosphorylation, subsequent dimerization, and binding to DNA of STAT1.
Other factors, including but not necessarily limited to CBP/p300, then bind within the C-terminal 38 amino acid transactivation
domain (TAD) to activate transcription. We show that both tyrosine-phosphorylated STAT1α (full-l...
Although mRNA decay rates are a key determinant of the steady-state concentration for any given mRNA species, relatively little is known, on a population level, about what factors influence turnover rates and how these rates are integrated into cellular decisions. We decided to measure mRNA decay rates in two human cell lines with high-density olig...
The c-fos gene was one of the earliest vertebrate genes shown to be transcriptionally induced by growth factors. Intensive study of
the promoter of c-fos(−325 to −80) by transient or permanent transfections of synthetic DNA constructs has repeatedly shown the importance of several
sequence elements and the resident nuclear proteins that bind them (...
The crystal structures of the N-terminal domain (N-domain) and the core region of the STAT family of transcription factors have been determined previously. STATs can form cooperative higher order structures (tetramers or higher oligomers) while bound to DNA. The crystal packing in the STAT4 N-domain crystal structure, determined at 1.5 A resolution...
In the Spring of 1991 Chris Schindler and X.Y. Fu in our lab had succeeded in purifying sufficiently ISGF3, the interferon-α induced DNA binding complex that David Levy had identified, so that we had some hope of identifying the constituent protein(s). The sizes of the proteins in ISGF3 were identified in an experiment that Dan Kessler and I cooked...
A limited list of transcription factors are overactive in most human cancer cells, which makes them targets for the development of anticancer drugs. That they are the most direct and hopeful targets for treating cancer is proposed, and this is supported by the fact that there are many more human oncogenes in signalling pathways than there are oncog...
The opportunity provided by the Albert Lasker Award for Special Achievement in Medical Science to reflect on my 'career' does not, I am sure, give me license to dwell on the humid, sweltering summers of a childhood in Mississippi. But perhaps I may be permitted to say a brief word of thanks to my teachers at the University of Mississippi, especiall...
Previously unrecognized mRNAs originating from a dual promoter at the stat92E locus are described. One of these encodes a truncated protein, DeltaNSTAT92E, that lacks the N-terminal 133 amino acids. Antibodies detect both the full-length and truncated molecules early in embryogenesis (1-5 h), and mRNA detection by specific RT-PCR reactions accords...
The STAT1 transcription factor is organized into several highly conserved domains, each of which has been assigned a function
with the exception of the linker domain. We previously characterized a mutant in the linker domain of STAT1 that gave normal
DNA binding using a standard probe in an electrophoretic mobility assay but failed to activate tran...
In response to IFN-gamma, the latent cytoplasmic protein signal transducers and activators of transcription 1 (Stat1) becomes phosphorylated on Y701, dimerizes, and accumulates in the nucleus to activate transcription of IFN-gamma-responsive genes. For maximal gene activation, S727 in the transcription activation domain of Stat1 also is inducibly p...
More than 2000 transcription factors are encoded in the human genome. Such proteins have often been classified according to
common structural elements. But because transcription factors evolved in the service of biologic function, we propose an alternative
grouping of eukaryotic transcription factors on the basis of characteristics that describe th...
Transcriptional activation by, and therefore the physiologic impact of, activated tyrosine-phosphorylated STATs (signal transducers and activators of transcription) may be negatively regulated by proteins termed PIAS (protein inhibitors of activated stats), as shown by previous experiments with mammalian cells in culture. Here, by using the genetic...
The STATs (signal transducers and activators of transcription), latent cytoplasmic transcription factors, are activated by
binding of extracellular polypeptides to cell surface receptors. Dimerization, accumulation in the nucleus, and transcriptional
inductions of specific genes then occur. The COOH terminus of the STATs acts as a transcriptional a...
The STAT proteins (Signal Transducers and Activators of Transcription), were identified in the last decade as transcription factors which were critical in mediating virtually all cytokine driven signaling. These proteins are latent in the cytoplasm and become activated through tyrosine phosphorylation which typically occurs through cytokine recepto...
Mannose 6-Phosphate Residues Target Proteins to LysosomesAnother function of some N-linked oligosaccharides is to target lysosomal
enzymes to lysosomes and prevent their secretion. The addition and initial processing of the
preformed N-linked oligosaccharide precursor in the rough ER is the same for
lysosomal enzymes as for membrane and secretory p...
Independent but closely spaced DNA binding sites for Stat3 and c-Jun are required for maximal enhancer function in a number of genes, including the gene encoding the interleukin-6 (IL-6)-induced acute-phase response protein, α
2
-macroglobulin. In addition, a physical interaction of Stat3 with c-Jun, based on yeast two-hybrid interaction experiment...
STATs are latent transcription factors that mediate cytokine- and growth factor-directed transcription. In many human cancers and transformed cell lines, Stat3 is persistently activated, and in cell culture, active Stat3 is either required for transformation, enhances transformation, or blocks apoptosis. We report that substitution of two cysteine...
Upon binding of gamma interferon (IFN-γ) to its receptor, the latent transcription factor Stat1 becomes phosphorylated, dimerizes,
and enters the nucleus to activate transcription. In response to IFN-α, Stat1 binds to Stat2 in a heterodimer that recruits
p48, an IRF family member, to activate transcription. A number of functional domains of the STA...
I am profoundly grateful to the American Society for Cell Biology for the award to me and my colleague Sheldon Penman of the E.B. Wilson Medal. This occasion presents the opportunity for reflections on a 40-year search for indications of how RNA functions as an informational molecule in eukaryotic cells. As will be recounted, this quest began in th...
The evolution of multicellular animals appears to be coincident with the development of a unique signalling device known as the Src-homology-2 (SH2) domain1. So named because of their original discovery in the genomes of sarcoma viruses, these protein modules are dedicated to the transmission of molecular signals that start at the cell surface and...
Excerpt
The STAT proteins are latent cytoplasmic transcriptionfactors that become tyrosine-phosphorylated by a varietyof intracellular kinases, most often in response to cytokines and growth factors (Schindler and Darnell 1995;Darnell 1997). Receptors with intrinsic tyrosine kinases(RTKs) may phosphorylate Stats directly or possibly actthrough othe...
The receptor tyrosine kinase Eyk, a member of the Axl/Tyro3 subfamily, activates the STAT pathway and transforms cells when constitutively activated. Here, we compared the potentials of the intracellular domains of Eyk molecules derived from c-Eyk and v-Eyk to transform rat 3Y1 fibroblasts. The v-Eyk molecule induced higher numbers of transformants...
Stat1alpha is a latent cytoplasmic transcription factor activated in response to interferon-gamma (IFN-gamma). The C-terminal 38 amino acids of Stat1alpha are required to trigger transcription and therefore may possibly serve as a transcription activation domain (TAD). Here we show that the C-terminus of Stat1alpha is an independent TAD which can i...
Sharing the Milstein Award with George R. Stark and Ian M. Kerr in the fall of 1997 brought this invitation to record personal reflections on our experiments concerning the mechanisms of action of interferon. Our work and that of the Kerr and Stark laboratories uncovered the Jak-Stat pathway through which signals from cell surface receptors reach g...
Epidermal growth factor (EGF) is a mitogen for most epithelial cells. Paradoxically, the growth of some cultured cell lines, containing high numbers of EGF receptors, are inhibited by EGF. Here we demonstrate that growth inhibition by EGF in several cell lines correlates with the activation of the signal transducer and activator of transcription (S...
The crystal structure of the DNA complex of a STAT-1 homodimer has been determined at 2.9 A resolution. STAT-1 utilizes a DNA-binding domain with an immunoglobulin fold, similar to that of NFkappaB and the p53 tumor suppressor protein. The STAT-1 dimer forms a contiguous C-shaped clamp around DNA that is stabilized by reciprocal and highly specific...
STATs (signal transducers and activators of transcription) are a family of transcription factors that are specifically activated to regulate gene transcription when cells encounter cytokines and growth factors. The crystal structure of an NH2-terminal conserved domain (N-domain) comprising the first 123 residues of STAT-4 was determined at 1.45 ang...
Gamma interferon (IFN-gamma) induces both tyrosine and serine phosphorylation of Stat1. Stat1 serine phosphorylation is required for maximal transcriptional activity of Stat1. In this report, we present evidence that Stat1 tyrosine phosphorylation is not a prerequisite for Stat1 serine phosphorylation, although an active Jak2 kinase is required for...
Systematists classify together three groups of organisms that are referred to as “slime molds,” the Myxogastria, Dictyostelia, and Protostelia (3). The Protostelids are the least studied. The Myxogastria include the well studied Physarum polycephalum, a prototypical single-celled ameba that can also form a large multinucleate plasmodium (4). Dictyo...
The STATs (signal transducers and activators of transcription) are latent cytoplasmic proteins that, upon activation by cell surface bound polypeptide ligands, move to the nucleus to direct transcription. A variety of protein-protein interactions that affect the function of STATs has been recently recognized. It has become clear that the STATs are...
Cytokine activation of gene expression can be mediated through signal transducer and activator of transcription (STAT) signaling pathways resulting in expression of target genes. Because many cytokines have important regulatory roles during early development, we wanted to ascertain whether STAT signaling was also active at this time and could there...
Recent work has shown that IL-10 induces activation of the JAK-STAT signaling pathway. To define the mechanism underlying signal transducer and activator of transcription (STAT) protein recruitment to the interleukin 10 (IL-10) receptor, the STAT proteins activated by IL-10 in different cell populations were first defined using electrophoretic mobi...
Leptin, a hormone secreted by adipocytes, regulates the size of the adipose tissue mass through effects on satiety and energy metabolism. Leptin's precise sites of action are not known. The leptin receptor (Ob-R) is found in many tissues in several alternatively spliced forms raising the possibility that leptin exerts effects on many tissues includ...
Type I (alpha, beta) and type II (gamma) interferons (IFNs) can restrict the growth of many cell types. INF-stimulated gene transcription, a key early event in IFN response, acts through the Janus kinase-signal transducers and activators of transcription pathway, in which both IFN-alpha and IFN-gamma activate the transcription factor Stat1. A cell...
![FIG. 5. Chimera Stat3/1[SH2], a Stat3 protein containing the Stat1 SH2...](profile/Peter-Heinrich-2/publication/14537696/figure/fig4/AS:443936570384388@1482854134135/Chimera-Stat3-1SH2-a-Stat3-protein-containing-the-Stat1-SH2-domain-exhibits-the-same_Q320.jpg)
Distinct yet overlapping sets of STAT transcription factors are activated by different cytokines. One example is the differential activation of acute phase response factor (APRF, also called Stat3) and Stat1 by interleukin 6 and interferon-gamma. Interleukin 6 activates both factors while, at least in human cells, interferon-gamma recruits only Sta...
A Drosophila Stat gene (D-Stat) with a zygotic segmental expression pattern was identified. This protein becomes phosphorylated on Tyr-704 when coexpressed in Schneider cells with a Drosophila janus kinase (JAK), Hopscotch (HOP). The phosphorylated protein binds specifically to the consensus sequence TTCCCGGAA. Suppressor mutations of hopTum-I, a d...
Studies of transcriptional activation by interferons and a variety of cytokines have led to the identification of a family of proteins that serve as signal transducers and activators of transcription, Stats. Here, we report that the seven mouse Stat loci map in three clusters, with each cluster located on a different mouse autosome. The data sugges...
Stat1 and Stat3 are latent transcriptional factors activated initially through phosphorylation on single tyrosine residues induced by cytokine and growth factor occupation of cell surface receptors. Here we show that phosphorylation on a single serine (residue 727) in each protein is also required for maximal transcriptional activity. Both cytokine...
Interleukin 12 (IL-12) initiates the differentiation of naive CD4+ T cells to T helper type 1 (Th1) cells critical for resistance to intracellular pathogens such as Leishmania major. To explore the basis of IL-12 action, we analyzed induction of nuclear factors in Th1 cells. IL-12 selectively induced nuclear DNA-binding complexes that contained Sta...
Activated monocytes play an important role in the pathogenesis of inflammatory arthritis. Blood monocytes which enter the inflamed joint become activated upon adherence to extracellular matrix and exposure to a complex inflammatory environment. We have analyzed the mechanism of monocyte activation by soluble factors present in inflammatory synovial...
The genomic structure of Stat2 has been determined and compared with a large portion of the Stat1 gene. There are 24 exons
in the Stat2 gene and a matching number In very similar positions in the Stat1 gene. Thus a very complicated genomic structure
was presumably duplicated and has been closely maintained throughout evolution.
The mechanisms by which GH regulates gene expression to alter growth and metabolism are unknown. We have demonstrated previously that in vivo GH treatment rapidly stimulates the tyrosine phosphorylation of multiple nuclear proteins and have identified the inducible transcription factor Stat1 (formerly Stat91) as one of the major GH-activated nuclea...
Molecular Cell Biology
Hepatocyte nuclear factor 4 (HNF-4) is a liver-enriched transcription factor and a member of the steroid hormone receptor superfamily. HNF-4 is required for the hepatoma-specific expression of HNF-1 alpha, another liver-enriched transcription factor, suggesting the early participation of HNF-4 in development. To prepare for further study of HNF-4 i...
Previous studies demonstrated that the intraperitoneal injection of epidermal growth factor (EGF) into mice resulted in the appearance, within minutes, of several tyrosine-phosphorylated proteins in liver nuclei. Two of these proteins have been identified as the transcription factors p91/p84 (Stat1 alpha/1 beta) (Ruff-Jamison, S., Chen, K., and Coh...
HNF-3 beta, a transcription factor of the winged-helix family, is expressed in embryonic and adult endoderm and also in midline cells of the node, notochord, and floor plate in mouse embryos. To define the function of HNF-3 beta, a targeted mutation in the HNF-3 beta locus was generated by homologous recombination in embryonic stem cells. Mice lack...
Binding of interferons IFN-alpha and IFN-gamma to their cell surface receptors promptly induces tyrosine phosphorylation of latent cytoplasmic transcriptional activators (or Stat proteins, for signal transducers and activators of transcription). Interferon-alpha activates both Stat91 (M(r) 91,000; ref. 1) and Stat113 (M(r) 113,000; ref. 2) whereas...
ICSBP, a member of the interferon regulatory factor family, is expressed predominantly in lymphoid tissues and is induced by gamma interferon (IFN-gamma). We have studied the genomic organization of the murine ICSBP gene and its 5' upstream region. The murine ICSBP gene (Icsbp) is present as a single copy on chromosome 8 and consists of nine exons....
CCAAT/enhancer-binding protein (C/EBP) is expressed in certain cell types including hepatocytes and adipocytes. In order to understand the mechanisms that control the expression of the mouse C/EBP gene in the liver as well as in adipocytes, we have studied both the endogenous gene and transfected C/EBP gene constructs. The initiation site of transc...
The interferon-alpha (IFN-alpha)-stimulated gene factor 3 (ISGF3), a transcriptional activator, contains three proteins, termed ISGF3 alpha proteins, that reside in the cell cytoplasm until they are activated in response to IFN-alpha. Treatment of cells with IFN-alpha caused these three proteins to be phosphorylated on tyrosine and to translocate t...
Alpha interferon stimulates transcription by converting the positive transcriptional regulator ISGF3 from a latent to an active form. This receptor-mediated event occurs in the cytoplasm, with subsequent translocation of the activated factor to the nucleus. ISGF3 has two components, termed ISGF3 alpha and ISGF3 gamma. ISGF3 gamma serves as the DNA...
The genes for rat hepatocyte nuclear factors 3 and 4 (HNF-3 alpha, HNF-3 beta, HNF-3 gamma, and HNF-4) have been mapped in mouse by analysis of restriction fragment length polymorphisms in interspecific backcross mice. These hepatocyte-enriched transcription factors are positive-acting transcription factors with binding sites in regulatory regions...
Significant advances in the field of hepatocyte-specific gene expression have been made during the past year. Several new transcription factors have been cloned and partially characterized. Analyses of the promoter regions of several factors have also been initiated and Drosophila homologs for two of these factors have been found, opening the way f...
Apolipoprotein CIII (apoCIII), a lipid-binding protein involved in the transport of triglycerides and cholesterol in the plasma, is synthesized primarily in the liver and the intestine. A cis-acting regulatory element, C3P, located at -90 to -66 upstream from the apoCIII gene transcriptional start site (+1), is necessary for maximal expression of t...
Although transcriptional hierarchies have been extensively studied in invertebrates, their involvement in mammalian cell-type specification is poorly understood. Here we report a hepatocyte transcriptional cascade suggested by the expression patterns of hepatic transcription factors in dedifferentiated hepatomas and hepatocyte: fibroblast hybrids i...
The promoters of two interferon-induced genes (the ISG54 and guanylate-binding protein [GBP] genes) have been analyzed in whole cells and in isolated nuclei by using a new genomic sequencing technique. The ISG54 gene contains an interferon-simulating response element (ISRE), earlier shown to be necessary and sufficient for alpha interferon (IFN-alp...
We previously demonstrated that glutamine synthetase (GS) and ornithine aminotransferase (OAT) mRNAs are expressed in the mouse liver acinus preferentially in pericentral hepatocytes, that is, those immediately surrounding terminal central veins (A.L. Bennett, K.E. Paulson, R.E. Miller, and J.E. Darnell, Jr., J. Cell Biol. 105:1073-1085, 1987, and...
The promoter of the gene encoding a cytoplasmic guanylate-binding protein (GBP) contains two overlapping elements: the interferon stimulation response element (ISRE), which mediates alpha interferon (IFN-alpha)-dependent transcription, and the IFN-gamma activation site (GAS), which is required for IFN-gamma-mediated stimulation. The ISRE binds a fa...
The gene encoding a 67-kDa cytoplasmic guanylate-binding protein (GBP) is transcriptionally induced in cells exposed to interferon of either type I (alpha interferon [IFN-alpha] or type II (IFN-gamma). The promoter of the GBP gene was cloned and found to contain an IFN-alpha-stimulated response element, which mediated the response of the GBP gene t...
The far-upstream mouse albumin enhancer (-10.5 to -8.43 kilobases) has both positive and negative regulatory domains which contribute to the rate and tissue specificity of albumin gene transcription. (R. S. Herbst, N. Friedman, J. E. Darnell, Jr., and L. E. Babiss, Proc. Natl. Acad. Sci. USA 86:1553-1557). In this work, the negative regulatory regi...
Interferon-stimulated gene factor 2 (ISGF2) was purified from HeLa cells treated with alpha interferon. The factor, a single polypeptide of 56 kilodaltons (kDa), bound both to the central 9 base pairs of the 15-base-pair interferon-stimulated response element (ISRE) that is required for transcriptional activation of interferon-stimulated genes and...
In situ hybridization and other data showed that all hepatocytes express glutathione-S-transferase (GST) Ya mRNA but that specifically pericentral cells can be induced 15- to 20-fold with 3-methylcholanthrene (3-MC). In order to identify DNA sequences involved in inducible expression (pericentral hepatocytes) and constitutive expression (all hepato...
Interferons (IFNs) play a key role in the defense against virus infection and the regulation of cell growth and differentiation, in part through changes in specific gene transcription in target cells. We describe several differences between the signal transduction events that result in transcriptional activation of the human gene coding for a guany...
Citations
... Tyrosine kinase 2 (TYK2) is a member of the Janus kinase (JAK) family of tyrosine kinases, which transduce cytokine-mediated signals through the JAK-STAT metabolic pathway [1,2]. Complete TYK2 deficiency has been previously described in patients with primary immunodeficiencies and Mendelian susceptibility to mycobacterial disease [3]. ...
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... Binding of ISGF3 to cellular genes containing ISREs is accompanied by changes in the chromatin structure of interferonstimulated genes (ISGs) (2). Cells incubated with IFN␣ show altered DNase I sensitivity surrounding the TATA box region as well as the ISRE of ISGs, suggesting that gene activation occurs as a result of chromatin remodeling (2). ...
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... Created with BioRender.com. All nine members of the IRF family have a conserved amino-terminal DNA-binding domain (DBD) [30][31][32][33][34][35] that recognizes the consensus DNA sequence element ISRE [36] in the gene promoters of IFNs and interferon-stimulated gene (ISG) genes [37]. These cytokines, in turn, activate antimicrobial and proinflammatory activities, as well as the maturation of antigen-specific adaptive immune responses. ...
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... This is important given that many of the "orphan" nuclear receptors like HNF4, COUP-TF and RXR share a common DNA binding motif consisting of a direct repeat of AGGTCA half sites (AGGTCAxAGGTCA). Indeed, competition for control of expression of liver-specific genes by HNF4a and other nuclear receptors was noted early on (73). The PBM studies also led to the identification of >60 unique, low affinity HNF4a binding sites located in more than a million Alu sequences which are unique to primate genomes; this raised the possibility of sequestration of HNF4a protein by binding repetitive genomic sequence as a novel mechanism by which to regulate HNF4a function (74). ...
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... JCI Insight 2024;9(11):e175278 https://doi.org/10.1172/jci.insight.175278 HNF-1A and HNF-4A form a crossregulatory loop, in which both factors regulate the respective other's gene transcription (Figure 1, A and B) (9)(10)(11)(12). Moreover, HNF-1A and HNF-4A interact physically and thereby further regulate gene transcription ( Figure 1B) (13)(14)(15). ...
... Jayakumar et al. [40] also documented up-regulation of guanylate binding proteins-1 and -2 (GBP-1 and GBP-2), as well as cyclooxygenase-2 genes. These genes were observed to be up-regulated in response to L. major infection [41,42] . These findings are associated with up-regulation of IL-12 levels that will manifest as a powerful healing response. ...
... The molecular bases for the metabolic zonation of liver parenchyma are not well known. They could include transcriptional and post-transcriptional events controlled by hormone and oxygen gradients, innervation, cellcell interactions etc. (Jungerman, 1988;Kuo and Darnell, 1991). The apparent discrepancy between zonation of 1600ABC/CAT transgene expression and the inapparent zona-tion of in vivo aldolase B activity could result from the in vivo stability of aldolase B contrasting with the lower stability of the CAT enzyme. ...
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... IRF8 is involved in polarization of T-cells. In antigenpresenting cells (APCs), IFN-g binding to IFNGR1/2 transactivates IRF8 expression through a STAT1-mediated pathway (72). IRF8 binds to the promoter region of IL12p40 and induces the production of IL-12 p40 from APCs, which promotes differentiation into Th1 cells (73,74). ...
... In previous work we found upregulation of GBP1 in breast cancer cells following coculturing with activated T lymphocytes [8]. The expression of GBP1 is under control of IFN-γ [33,34] and blocking of the IFN-γ pathway with inhibitor doses ≥ 5 µg/ml significantly decreased GBP1 expression (Supplemental figure 2) and significantly decreased passage of breast cancer cells through our in vitro BBB model (Fig 3a). These data are in line with the assumption that GBP1 expression, dependent on IFN-γ, is linked with increased motility of the cells [35,36]. ...
... Among the 26 genes that were commonly upregulated in the four bat cell lines (Supplemental Table 2), RIG-I (DDX58) and LGP2 (DHX58), members of the RIG-I-like receptor family, recognize viral-derived double-stranded RNA and induce the production of type I interferons (Kato et al., 2008). Interferon regulatory factors IRF1 and IRF7 also induce the production of type I interferons (Andrilenas et al., 2018;Pine et al., 1990). Therefore, it is expected that the production and response of type I interferons occur in the four bat cell types. ...
