Inducibility of κ immunoglobulin enhancer-binding protein NF-κB by a posttranslational mechanism

Sen, Ranjan; Baltimore, David

doi:10.1016/0092-8674(86)90807-x

Cited by 1,922 publications

(1,211 citation statements)

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“…A number of interactions or modifications might occur during embryogenesis to change the behaviour of regulators. For example, phosphorylation can potentially produce 40 or unmask 41,42 acidic domains that activate transcription 43 . Accordingly, ftz and en, both of which are known to be phosphorylated 44,45 , might not always have the same transcriptional effects that we have observed in these experiments.…”

Section: Discussionmentioning

confidence: 99%

Activation and repression of transcription by homoeodomain-containing proteins that bind a common site

Jaynes

O’Farrell

1988

Nature

223

148

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The product of the fushi tarazu (ftz) gene is shown to be a site-dependent activator of transcription. In vitro-defined binding sites act as ftz-dependent enhancers in cultured cells. Another homoeodomain-containing protein, the engrailed gene product, competes for homoeodomainbinding sites and counteracts ftz activation.GENETIC analysis in Drosophila melanogaster has identified a group of regulatory genes that participate in embryonic pattern formation 1,2 . Many of these genes encode a 60 amino-acid sequence, the homoeodomain, that is highly conserved through evolution [3][4][5] . This domain contains a putative helix-turn-helix motif 6 such as that found in a number of bacterial regulators 7 , and possesses a sequence-specific DNA-binding activity 8,9 . Numerous regulatory interactions occur among homoeodomain-encoding genes during development. For example, a combination of segmentation and homoeotic gene products, many of which contain homoeodomains 1 , specify the developmental fates of cells in striped patterns 10,11 . Furthermore, homoeodomain-containing proteins (homoeodomain proteins) regulate both each other 12 and downstream (`cytodifferentiation' 13 ) genes. Consequently, it has been attractive to think of homoeodomain proteins as direct regulators of transcription. Due to the complexity of cross-regulatory interactions however, mutations altering or eliminating one homoeodomain protein generally change the expression patterns of many other regulators, confounding efforts to distinguish direct from indirect regulation. Additionally, suspected target genes contain large cis-acting control regions that respond, directly or indirectly, to complex combinations of regulators [14][15][16][17] . As a result, identification of target genes directly regulated by homoeodomain proteins has been problematic.Previous studies have documented instances in which homoeodomain proteins control transcription. The enhancer activity of a DNA fragment from the ftz gene, a homoeodomaincontaining member of the pair-rule class of segmentation genes, suggested that the ftz gene product (ftz) activates its own expression in the embryo 18 . In a different approach a Drosophila tissue culture system was used to show that the Ultrabithorax (Ubx) gene product induces expression of its own promoter, and inhibits the Antennapedia (Antp) (P1) promoter (M. Krasnow and D. S. Hogness, personal communication, see ref. 19 for summary). In these cases however, the complexity of the regulatory circuitry and of the responding control regions leaves open the possibility that the homoeodomain proteins produce these transcriptional effects through intermediaries. To circumvent the complexities of natural target genes, we chose to use binding sites identified in vitro to build homoeodomain-responsive promoters. We find that ftz is a potent activator of transcription from these promoters in cultured cells.During sequential subdivision of the Drosophila embryo to produce segmentally repeating patterns, combinations of regulatory gene prod...

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Section: Discussionmentioning

confidence: 99%

Activation and repression of transcription by homoeodomain-containing proteins that bind a common site

Jaynes

O’Farrell

1988

Nature

223

148

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“…DNA mobility shift assays were performed as originally described by Sen and Baltimore [45]. The MMTV GRE [46] consists of base pairs from −191 to −159 of the MMTV-LTR and has the following sequence: 5 -GTT, TAT, GGT, TAC, AAA, CTG, TTC, TTA, AAA, CAA, GGA-3 .…”

Section: Electrophoretic Mobility Shift Assay (Emsa)mentioning

confidence: 99%

Vanadate increases glucocorticoid receptor-mediated gene expression: a novel mechanism for potentiation of a steroid receptor

Calzi

Periyasamy

et al. 2002

The Journal of Steroid Biochemistry and Molecular Biology

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Transition metal oxyanions, such as molybdate, tungstate and vandadate, have been shown to prevent in vitro hormone-induced activation of the glucocorticoid receptor (GR) by blocking dissociation of the GR/heat shock protein heterocomplex. In this work, we report a novel effect of vanadate: in vivo potentiation of GR-mediated gene expression. In cells stably-transfected with complex (mouse mammary tumor virus (MMTV)) or minimal GR-regulated CAT reporters, treatment with 500 M vanadate caused CAT gene expression to dramatically increase, even at saturating concentrations of dexamethasone; while no such effect was seen in response to RU486 antagonist. Similar treatment with molybdate had no effect on GR activity, suggesting that the response to vanadate was not a general property of transition metal oxyanions. Treatment with vanadate after hormone-induced nuclear translocation of the GR also caused potentiation, demonstrating that vanadate was acting on a post-transformation event, perhaps by affecting the transactivation function of DNA-bound GR. Paradoxically, vanadate caused an apparent but temporary "loss" of GR protein immediately after treatment (as measured by loss of reactivity to BuGR2 antibody and of hormone-binding capacity) that returned to normal at approximately 8 h post-treatment, suggesting that potentiation of GR transactivation function (as measured by our CAT assays) was probably occurring during the later stages (8-24 h) of this assay. However, gel shift analyses revealed that vanadate could induce binding of the hormone-free GR to glucocorticoid response element (GRE)-containing oligonucleotides immediately after treatment. Thus, the rapid vanadate-induced "loss" of GR was not due to degradation of GR protein. Yet, vanadate in the absence of hormone had no effect on CAT reporter expression, demonstrating that this form of the GR still requires agonist for its enhanced transcriptional activity. As an indication of the potential mechanism of vanadate action, vanadate was found to dramatically stimulate the mitogen-activated protein kinases, ERK-1 and ERK-2. In addition, vanadate potentiation of GR reporter gene expression was completely blocked by the tyrosine kinase inhibitor herbimycin A. Taken as a whole, our results suggest that vanadate can have dramatic and complex effects on GR structure and function, resulting in hormone-free activation of GR DNA-binding function, as well as alterations to the BuGR2 epitope and hormone-binding domains-while at the same time stimulating tyrosine phosphorylation pathways controlling GR-mediated gene transcription.

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“…11 Following the first description in B cells, NF-kB was quickly demonstrated to be a member of a ubiquitously expressed family of Rel-related transcription factors capable of regulating the transcription of a large variety of genes involved in apoptosis, cell growth, response to inflammatory and stress signals, limb development, bone remodeling and immune response. [12][13][14] We tested the effect of four inhibitors affecting the steps of the NF-kB activation cascade at the levels described schematically in Figure 1. The antioxidants Nacetyl-L-cysteine (NAC) and pyrrolidine dithiocarbamate (PTDC) prevent the increase of reactive oxygen intermediates capable of stimulating Ik-Bs degradation.…”

Section: Moter Adcftr Also Stimulated a 13-fold Increase In Nfkb-dementioning

confidence: 99%

Activation of NF-kB mediates ICAM-1 induction in respiratory cells exposed to an adenovirus-derived vector

et al. 2001

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Gene transfer to the respiratory tract by replication-deficient adenoviruses is limited by the induction of inflammatory and immune responses. We previously demonstrated that a E1-E3-deleted recombinant adenovirus carrying the expression cassette for the cystic fibrosis gene (Ad.CFTR) upregulates the expression of the pro-inflammatory intercellular adhesion molecule-1 (ICAM-1) both in vitro and in vivo. In the present work we suggest a role for the nuclear factor-kB (NF-kB) in Ad.CFTR-dependent up-regulation of ICAM-1 in respiratory epithelial A549 cells. Specifically, Ad.CFTR induced translocation of NF-kB into the nucleus and binding to the proximal −228/−218 NF-kB consensus sequence on the ICAM-1 pro-

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Inducibility of κ immunoglobulin enhancer-binding protein NF-κB by a posttranslational mechanism

Cited by 1,922 publications

References 48 publications

Activation and repression of transcription by homoeodomain-containing proteins that bind a common site

Activation and repression of transcription by homoeodomain-containing proteins that bind a common site

Vanadate increases glucocorticoid receptor-mediated gene expression: a novel mechanism for potentiation of a steroid receptor

Activation of NF-kB mediates ICAM-1 induction in respiratory cells exposed to an adenovirus-derived vector

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