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Author

Bernd Groner

Bio: Bernd Groner is an academic researcher from University of California, San Francisco. The author has contributed to research in topics: STAT protein & Gene. The author has an hindex of 64, co-authored 163 publications receiving 11899 citations.
Topics: STAT protein, Gene, STAT5, Cytotoxic T cell, STAT3


Papers
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Journal ArticleDOI
09 Jul 1998-Nature
TL;DR: The first crystal structure of a STAT protein bound to its DNA recognition site at 2.25 Å resolution is reported, providing insight into the various steps by which STAT proteins deliver a response signal directly from the cell membrane to their target genes in the nucleus.
Abstract: STAT proteins are a family of eukaryotic transcription factors that mediate the response to a large number of cytokines and growth factors. Upon activation by cell-surface receptors or their associated kinases, STAT proteins dimerize, translocate to the nucleus and bind to specific promoter sequences on their target genes. Here we report the first crystal structure of a STAT protein bound to its DNA recognition site at 2.25 A resolution. The structure provides insight into the various steps by which STAT proteins deliver a response signal directly from the cell membrane to their target genes in the nucleus.

774 citations

Journal ArticleDOI
24 Oct 1996-Nature
TL;DR: It is shown here that the glucocorticoid receptor can act as a transcriptional co-activator for Stat5 and enhance Stat5-dependent transcription.
Abstract: SIGNAL transduction pathways enable extracellular signals to activate latent transcription factors in the cytoplasm of cells. Dimerization, nuclear localization and binding to specific DNA sequences result in the induction of gene transcription by these proteins. These events are necessary for the functioning of the JAK/STAT pathway and of the glucocorticoid-receptor pathway. In the former, the protein Stat5, which is a member of a family of signal transducers and activators of transcription, is activated by cytokines, hormones and growth factors1–7. These polypeptide ligands bind at the outside of the cell to specific transmembrane receptors and activate intracellular Janus protein tyrosine kinases (JAKs) to tyrosine-phosphorylate STAT proteins; interaction with the SH2 domain of the dimerization partner then confers the ability to bind to DNA at the STAT-response element and induce transcription8–10. In the glucocorticoid-receptor path-way, the receptor interacts with its steroid hormone ligand in the cytoplasm, undergoes an allosteric change that enables the hormone receptor complex to bind to specific DNA-response elements (glucocorticoid response elements, or GRE) and mod-ulate transcription11,12. Although these pathways appear to be unrelated, we show here that the glucocorticoid receptor can act as a transcriptional co-activator for Stat5 and enhance Stat5-dependent transcription. Stat5 forms a complex with the gluco-corticoid receptor which binds to DNA independently of the GRE. This complex formation between Stat5 and the glucocorticoid receptor diminishes the glucocorticoid response of a GRE-con-taining promoter.

672 citations

Journal ArticleDOI
TL;DR: The increase of Stat5 expression during pregnancy coincides with the activation of the WAP gene, and the two RNAs are present in mammary tissue of immature virgin mice, and their levels increase up to day 16 of pregnancy, followed by a decline during lactation.
Abstract: Prolactin (PRL) induces transcriptional activation of milk protein genes, such as the whey acidic protein (WAP), beta-casein, and beta-lactoglobulin genes, through a signaling cascade encompassing the Janus kinase Jak2 and the mammary gland factor (MGF; also called Stat5), which belongs to the family of proteins of signal transducers and activators of transcription (STAT). We isolated and sequenced from mouse mammary tissue Stat5 mRNA and a previously unreported member, which we named Stat5b (Stat5 is renamed to Stat5a). On the protein level Stat5a and Stat5b show a 96% sequence similarity. The 5' and 3' untranslated regions of the two mRNAs are not conserved. Stat5a comprises 793 amino acids and is encoded by a mRNA of 4.2 kb. The Stat5b mRNA has a size of 5.6 kb and encodes a protein of 786 amino acids. Both Stat5a and Stat5b recognized the GAS site (gamma-interferon-activating sequence; TTCNNNGAA) in vitro and mediated PRL-induced transcription in COS cells transfected with a PRL receptor. Stat5b also induced basal transcription in the absence of PRL. Similar levels of Stat5a and Stat5b mRNAs were found in most tissues of virgin and lactating mice, but a differential accumulation of the Stat5 mRNAs was found in muscle and mammary tissue. The two RNAs are present in mammary tissue of immature virgin mice, and their levels increase up to day 16 of pregnancy, followed by a decline during lactation. The increase of Stat5 expression during pregnancy coincides with the activation of the WAP gene.

530 citations

Journal ArticleDOI
01 Mar 1996-Blood
TL;DR: The presence of constitutively activated STAT factors in peripheral blood cells from patients with acute leukemia is described and it is likely that the constitutive activation of STAT proteins is a part of the events of leukemogenesis.

340 citations

Journal ArticleDOI
TL;DR: It is proposed that Stat5a delta 750 and Stat5b delta 754 are lacking functional transactivation domains and exert their dominant negative effects by blocking the DNA-binding site in Stat5-responsive gene promoters.
Abstract: The Stat (signal transducer and activator of transcription) factors transmit cytokine, growth factor, and hormone responses. Seven members of the Stat gene family are known. MGF-Stat5a has been discovered as a mediator of the prolactin response in mammary epithelial cells. Two closely related variants of Stat5, Stat5a and Stat5b, are encoded by distinct genes. We examined the functional properties of the carboxyl termini of these molecules. Wild-type Stat5a (794 amino acids) and the carboxyl-terminal deletion mutant Stat5a delta 772 supported prolactin-induced transcription of a beta-casein promoter-reporter construct in COS7 cells; Stat5a delta 750 did not. Upon prolactin activation, tyrosine phosphorylation and the specificity of DNA binding were indistinguishable among the three Stat5a variants. Tyrosine dephosphorylation and the downregulation of the DNA-binding activity were delayed in the Stat5a delta 750 mutant. The carboxyl-terminal transactivation domain of Stat5a, amino acids 722 to 794, can be conferred to the DNA-binding domain of the yeast transcription factor GAL4. Coexpression of Stat5a or Stat5b and of the carboxyl-terminal deletion mutants resulted in the suppression of transcriptional induction in COS or Ba/F3 cells. We propose that Stat5a delta 750 and Stat5b delta 754 are lacking functional transactivation domains and exert their dominant negative effects by blocking the DNA-binding site in Stat5-responsive gene promoters.

276 citations


Cited by
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Journal ArticleDOI
TL;DR: This review considers recent findings regarding GC action and generates criteria for determining whether a particular GC action permits, stimulates, or suppresses an ongoing stress-response or, as an additional category, is preparative for a subsequent stressor.
Abstract: The secretion of glucocorticoids (GCs) is a classic endocrine response to stress. Despite that, it remains controversial as to what purpose GCs serve at such times. One view, stretching back to the time of Hans Selye, posits that GCs help mediate the ongoing or pending stress response, either via basal levels of GCs permitting other facets of the stress response to emerge efficaciously, and/or by stress levels of GCs actively stimulating the stress response. In contrast, a revisionist viewpoint posits that GCs suppress the stress response, preventing it from being pathologically overactivated. In this review, we consider recent findings regarding GC action and, based on them, generate criteria for determining whether a particular GC action permits, stimulates, or suppresses an ongoing stressresponse or, as an additional category, is preparative for a subsequent stressor. We apply these GC actions to the realms of cardiovascular function, fluid volume and hemorrhage, immunity and inflammation, metabolism, neurobiology, and reproductive physiology. We find that GC actions fall into markedly different categories, depending on the physiological endpoint in question, with evidence for mediating effects in some cases, and suppressive or preparative in others. We then attempt to assimilate these heterogeneous GC actions into a physiological whole. (Endocrine Reviews 21: 55‐ 89, 2000)

6,707 citations

Journal ArticleDOI
TL;DR: Findings that have advanced the understanding of IL-10 and its receptor are highlighted, as well as its in vivo function in health and disease.
Abstract: Interleukin-10 (IL-10), first recognized for its ability to inhibit activation and effector function of T cells, monocytes, and macrophages, is a multifunctional cytokine with diverse effects on most hemopoietic cell types. The principal routine function of IL-10 appears to be to limit and ultimately terminate inflammatory responses. In addition to these activities, IL-10 regulates growth and/or differentiation of B cells, NK cells, cytotoxic and helper T cells, mast cells, granulocytes, dendritic cells, keratinocytes, and endothelial cells. IL-10 plays a key role in differentiation and function of a newly appreciated type of T cell, the T regulatory cell, which may figure prominently in control of immune responses and tolerance in vivo. Uniquely among hemopoietic cytokines, IL-10 has closely related homologs in several virus genomes, which testify to its crucial role in regulating immune and inflammatory responses. This review highlights findings that have advanced our understanding of IL-10 and its receptor, as well as its in vivo function in health and disease.

6,308 citations

Journal ArticleDOI
TL;DR: Control elements of the tetracycline-resistance operon encoded in Tn10 of Escherichia coli have been utilized to establish a highly efficient regulatory system in mammalian cells that is suitable for creation of "on/off" situations for such genes in a reversible way.
Abstract: Control elements of the tetracycline-resistance operon encoded in Tn10 of Escherichia coli have been utilized to establish a highly efficient regulatory system in mammalian cells. By fusing the tet repressor with the activating domain of virion protein 16 of herpes simplex virus, a tetracycline-controlled transactivator (tTA) was generated that is constitutively expressed in HeLa cells. This transactivator stimulates transcription from a minimal promoter sequence derived from the human cytomegalovirus promoter IE combined with tet operator sequences. Upon integration of a luciferase gene controlled by a tTA-dependent promoter into a tTA-producing HeLa cell line, high levels of luciferase expression were monitored. These activities are sensitive to tetracycline. Depending on the concentration of the antibiotic in the culture medium (0-1 microgram/ml), the luciferase activity can be regulated over up to five orders of magnitude. Thus, the system not only allows differential control of the activity of an individual gene in mammalian cells but also is suitable for creation of "on/off" situations for such genes in a reversible way.

5,322 citations

Journal ArticleDOI
TL;DR: The Janus kinases and signal transducers and activators of transcription, and many of the interferon-induced proteins, play important alternative roles in cells, raising interesting questions as to how the responses to the interFERons intersect with more general aspects of cellular physiology and how the specificity of cytokine responses is maintained.
Abstract: Interferons play key roles in mediating antiviral and antigrowth responses and in modulating immune response. The main signaling pathways are rapid and direct. They involve tyrosine phosphorylation and activation of signal transducers and activators of transcription factors by Janus tyrosine kinases at the cell membrane, followed by release of signal transducers and activators of transcription and their migration to the nucleus, where they induce the expression of the many gene products that determine the responses. Ancillary pathways are also activated by the interferons, but their effects on cell physiology are less clear. The Janus kinases and signal transducers and activators of transcription, and many of the interferon-induced proteins, play important alternative roles in cells, raising interesting questions as to how the responses to the interferons intersect with more general aspects of cellular physiology and how the specificity of cytokine responses is maintained.

4,026 citations