rel Gene control of lipid synthesis in Escherichia coli. Evidence for eliminating fatty acid synthesis as the sole regulatory site.
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Amino Acids↗
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A consequence of the rel gene during a glucose to lactate downshift in Escherichia coli. The rates of ribonucleic acid synthesis.
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Adenosine Triphosphate↗
Mutations of tumor necrosis factor alpha-responsive serine residues within the C-terminal transactivation domain of human transcription factor REL enhance its in vitro transforming ability.
The human c-rel gene (REL), encoding an NF-kappaB transcription factor, is amplified or mutated in several human B-cell lymphomas and can transform chicken lymphoid cells in vitro. We have previously shown that certain deletions of C-terminal transactivation sequences enhance REL's transforming ability in chicken spleen cells. In this report, we have analysed the effect of single amino-acid changes at select serine residues in the C-terminal transactivation domain on REL's transforming ability. Mutation of either of two TNFalpha-inducible serine residues (Ser460 and Ser471) to nonphosphorylatable residues (alanine, asparagine, phenylalanine) made REL more efficient at transforming chicken spleen cells in vitro. In contrast, mutation of Ser471 to a phosphorylation mimetic aspartate residue impaired REL's transforming ability, even though it increased REL's inherent transactivation ability as a GAL4-fusion protein. Alanine mutations of several other serine residues within the transactivation domain did not substantially affect REL's transforming ability. Transactivation by GAL4-REL fusion proteins containing either transformation enhancing or nonenhancing mutations at serine residues was generally similar to wild-type GAL4-REL. However, more transforming mutants with mutations at either Ser460 or Ser471 differed from wild-type REL in their ability to transactivate certain kappaB-site reporter genes. In particular, the SOD2 promoter, encoding manganese superoxide dismutase, was activated less strongly by the more transforming REL mutant REL-S471N in transient assays, but REL-S471N-transformed chicken spleen cells had increased levels of MnSOD protein as compared to wild-type REL-transformed cells. Taken together, our results show that mutations of certain serine residues can enhance REL's transforming ability in vitro and suggest that these mutations increase REL-mediated transformation by altering REL's ability to modulate the expression of select target genes. Furthermore, phosphorylation of Ser471 may be involved in REL-mediated modulation of transformation-specific target gene expression. Lastly, these results suggest that similar mutations in the REL transactivation domain contribute to the development of certain human B-cell lymphomas.
Animals↗
Overexpression of a novel Xenopus rel mRNA gene induces tumors in early embryos.
The Rel family of transcriptional activators form a large diverse group of proteins that are involved in the activation of genes involved in immunity, development, apoptosis and cancer. So far, none of the rel genes cloned in mammals appear to be required for embryonic development. We have cloned and characterized a cDNA from an embryonic cDNA library that encodes a novel Xenopus Rel protein, called Xrel3. Xrel3 is a member of the cRel subfamily and is most closely related to but distinct from other Xenopus Rel members. The expression of Xrel3 mRNA was investigated using Northern analysis, RNase protection assay, reverse transcriptase-linked polymerase chain reaction and in situ hybridization. Messages are present maternally and are slightly enriched in the equatorial region of the blastula stage embryo. At gastrulation, the accumulation of Xrel3 messages declines to undetectable levels but then increases after neurulation. In situ RNA hybridization was used to determine the spatial location of Xrel3 messenger RNA in embryos. Messages are localized to the developing forebrain, dorsal mid-hindbrain region, the inner ear primordium, or otocyst, and in the notochord. Overexpression by microinjection of Xrel3 RNA induced tumors in the developing embryo that appeared after gastrulation. The location of the tumors depended on the location of the injection site. These results suggest that Xrel3 might have a generalized role in regulation of cell differentiation in the embryo.
Amino Acid Sequence↗
Role of rel family genes in normal and malignant lymphoid cell growth.
The rel family of genes encodes transcription factors, such as the v-rel oncoprotein and cellular transcription complexes (eg NF-kappa B), consisting of c-rel and related polypeptides. The expression of these genes is correlated most closely with lymphoid cell differentiation and growth stimulation in a variety of cell types. Similarly, rel family proteins control a number of genes involved in lymphoid cell growth and differentiation. Thus, it is not surprising that mutations in rel genes have been implicated directly and circumstantially in a number of lymphoid malignancies, as have a number of other cellular and viral transcription factors (see also Cleary M, Hayman M and Beug H, this issue and reviewed in Rabbitts, 1991). In addition, rel proteins are likely to be involved in T cell diseases caused by the human retroviruses HTLV-I and HIV-1. Therefore, rel proteins could serve as targets for anti-viral or anti-cancer therapies.
Gene Expression↗
The relA/spoT-homologous gene in Streptomyces coelicolor encodes both ribosome-dependent (p)ppGpp-synthesizing and -degrading activities.
Streptomyces coelicolor (p)ppGpp synthetase (Rel protein) belongs to the RelA and SpoT (RelA/SpoT) family, which is involved in (p)ppGpp metabolism and the stringent response. The potential functions of the rel gene have been examined. S. coelicolor Rel has been shown to be ribosome associated, and its activity in vitro is ribosome dependent. Analysis in vivo of the active recombinant protein in well-defined Escherichia coli relA and relA/spoT mutants provides evidence that S. coelicolor Rel, like native E. coli RelA, is functionally ribosome associated, resulting in ribosome-dependent (p)ppGpp accumulation upon amino acid deprivation. Expression of an S. coelicolor C-terminally deleted Rel, comprised of only the first 489 amino acids, catalyzes a ribosome-independent (p)ppGpp formation, in the same manner as the E. coli truncated RelA protein (1 to 455 amino acids). An E. coli relA spoT double deletion mutant transformed with S. coelicolor rel gene suppresses the phenotype associated with (p)ppGpp deficiency. However, in such a strain, a rel-mediated (p)ppGpp response apparently occurs after glucose depletion, but only in the absence of amino acids. Analysis of ppGpp decay in E. coli expressing the S. coelicolor rel gene suggests that it also encodes a (p)ppGpp-degrading activity. By deletion analysis, the catalytic domains of S. coelicolor Rel for (p)ppGpp synthesis and degradation have been located within its N terminus (amino acids 267 to 453 and 93 to 397, respectively). In addition, E. coli relA in an S. coelicolor rel deletion mutant restores actinorhodine production and shows a nearly normal morphological differentiation, as does the wild-type rel gene, which is in agreement with the proposed role of (p)ppGpp nucleotides in antibiotic biosynthesis.
Anthraquinones↗
A genomewide survey of developmentally relevant genes in Ciona intestinalis. III. Genes for Fox, ETS, nuclear receptors and NFkappaB.
A survey against the draft genome sequence and the cDNA/EST database of Ciona intestinalis identified a number of genes encoding transcription factors regulating a variety of processes including development. In the present study, we describe almost complete sets of genes for Fox, ETS-domain transcription factors, nuclear receptors, and NFkappaB as well as other factors regulating NFkappaB activity, with their phylogenetic nature. Vertebrate Fox transcription factors are currently delineated into 17 subfamilies: FoxA to FoxQ. The present survey yielded 29 genes of this family in the Ciona genome, 24 of which were Ciona orthologues of known Fox genes. In addition, we found 15 ETS genes, 17 nuclear receptor genes, and several NFkappaB signaling pathway genes in the Ciona genome. The number of Ciona genes in each family is much smaller than that of vertebrates, which represents a simplified feature of the ascidian genome. For example, humans have two NFkappaB genes, three Rel genes, and five NFAT genes, while Ciona has one gene for each family. The Ciona genome also contains smaller numbers of genes for the NFkappaB regulatory system, i.e. after the split of ascidians/vertebrates, vertebrates evolved a more complex NFkappaB system. The present results therefore provide molecular information for the investigation of complex developmental processes, and an insight into chordate evolution.
Animals↗
Myb proteins inhibit fibroblast transformation by v-Rel.
Genes that cause cancer have been divided into two general classes--oncogenes that act in a dominant fashion to transform normal cells into a malignant state, and tumor suppressor genes that act in a dominant fashion to prevent such transformation. In this report, we demonstrate that both the v-myb retroviral oncogene, which causes leukemic transformation of hematopoietic cells, and the c-myb proto-oncogene can also function as inhibitors of fibroblast transformation by the v-rel oncogene. These results imply that the myb genes can function either as oncogenes or as tumor suppressors in different cellular contexts.
Actins↗
Effect of the "ribonucleic acid control" locus in Escherichia coli on T4 bacteriophage-specific ribonucleic acid synthesis.
Amino acid control of ribonucleic acid (RNA) synthesis in bacteria is known to be governed genetically by the rel locus. We investigated whether the rel gene of the host would also exert its effect on the regulation of phage-specific RNA synthesis in T4 phage-infected Escherichia coli cells. Since T-even phage infection completely shuts off host macromolecular synthesis, phage RNA synthesis could be followed specifically by the cumulative incorporation of radioactivity from labeled precursors into RNA of infected cells. Labeled uracil was shown to accumulate in phage-specific RNA for 30 to 35 min after infection, a phenomenon which probably reflects an expansion of the labile phage-RNA pool. Amino acid starvation was effected by the use of auxotrophic bacterial strains or thienylalanine. The latter substance is an amino acid analogue which induces a chemical auxotrophy by inhibiting the biosynthesis of phenylalanine, tyrosine, and tryptophan. Phage RNA synthesis was strictly dependent on the presence of amino acids, whereas phage deoxyribonucleic acid synthesis was not. By the use of several pairs of bacterial strains which were isogenic except for the rel gene, it was demonstrated that amino acid dependence was related to the allelic state of this gene. If the rel gene was mutated, amino acid starvation did not restrict phage RNA synthesis.
Amino Acids↗
Mutational analysis of v-rel, the oncogene of reticuloendotheliosis virus strain T.
Reticuloendotheliosis virus strain T (Rev-T) is a highly oncogenic retrovirus that induces a lethal lymphoma in young galliform birds and also transforms and immortalizes avian lymphoid cells in vitro. Rev-T presumably arose when a reticuloendotheliosis virus (Rev) incorporated a portion of the turkey c-rel gene into its genome, forming the v-rel oncogene. The predicted v-rel protein (p59v-rel) has 14 amino acid substitutions and 3 amino acid deletions relative to the predicted turkey c-rel protein. The 5' Rev env-derived amino-terminus of p59v-rel also has amino acid substitutions in codons 3, 6, and 9 relative to wild-type Rev-A env. To distinguish the critical alterations from the neutral ones, we made a mutation that resulted in a substitution of the 5' Rev env-derived amino-terminus by a single methionine, as well as several back-mutations, in the context of an otherwise wild-type v-rel and tested the transforming, immortalizing, and tumorigenic properties of the resulting proteins. All proteins tested retained the transforming, immortalizing, and tumorigenic functions of v-rel. Absence of the 5' Rev env-derived amino-terminus, as well as back-mutations of six of the amino acid changes present in the rel-derived amino-terminal and central regions of v-rel, reduced transformation efficiency. The mutations present in codons 3, 6, and 9 of p59v-rel showed complicated interactions in their activating effects on transformation efficiency. We also showed that loss of the immortalizing function did not abolish tumorigenesis by v-rel. We further showed that the primary transduction event involving the turkey c-rel gene could have occurred with a replication-competent Rev having v-rel-specific mutations in codons 3, 6, and 9 of the env gene.
Amino Acid Sequence↗
Identification and characterization of rel promoter element of Mycobacterium tuberculosis.
The rel gene is responsible for the maintenance of the level of (p)ppGpp in bacteria under nutrient starvation. This phenomenon known as stringent response plays an important role during survival of the microorganisms in stationary phase. We have cloned 1.6 kb upstream sequence of rel gene of Mycobacterium tuberculosis in a shuttle vector pSD5B containing promoterless lacZ gene and promoter activity was observed in Mycobacterium smegmatis cells by blue/white selection and was measured by beta-galactosidase assay. In order to delineate the minimal promoter element of rel gene, a 200 bp fragment from this 1.6 kb upstream sequence was further cloned in promoterless lacZ shuttle vector pSD5B and promoter activity was observed in M. smegmatis cells in similar way. The 200 bp promoter fragment was found to be mycobacterium specific and did not respond when transformed in Escherichia coli. The +1 transcription start site was determined by primer extension method. The -10 promoter region was identified to be TATCCT. The three T bases when mutated, showed a remarkable decrease in the lacZ expression thus confirming the -10 region. The translation start site has also been identified by site directed frame shift mutagenesis. It appears that this rel promoter can be used for expression of proteins in mycobacteria.
5' Flanking Region↗
Enforced c-REL deficiency prolongs survival of islet allografts1.
BACKGROUND: The NF-kappaB/Rel family of transcription factors regulates biologic processes ranging from apoptosis to inflammation and innate immunity. Whether c-Rel, a lymphoid-predominant member of the NF-kappaB/Rel family, is essential for transplantation immunity is not known. METHODS: We explored the role of c-Rel in the anti-allograft repertory using mice with targeted disruption of the c-Rel gene (c-Rel-/-) as recipients of H-2 mismatched islet allografts. Allogeneic DBA/2 (H-2d) islets were transplanted into the renal subcapsular space of diabetic c-Rel-/- C57BL/6 (H-2b) mice or the c-Rel +/+ C57BL/6 wild-type mice. Islet graft survival, cellular traffic into the islet grafts and their phenotype, and intragraft expression of cytokines and cytotoxic attack molecules were determined at the protein (by immunohistochemistry) and mRNA (by real-time quantitative polymerase chain reaction) levels. RESULTS: We found superior islet graft survival in the c-Rel-/- recipients compared to c-Rel+/+ C57BL/6 recipients. Splenocytes from c-Rel-/- mice proliferated poorly compared to splenocytes from the c-Rel+/+ mice on stimulation with anti-CD3 mAbs or Con A. Peri-islet infiltration composed of T lymphocytes and macrophages was found in both c-Rel+/+ recipients and c-Rel-/- recipients, but intra-islet infiltration was observed only in c-Rel+/+ recipients. Immunohistologic and molecular studies showed impaired T helper-type 1 immunity and decreased intragraft expression of cytotoxic attack molecules perforin and granzyme B in c-Rel-/- recipients as compared to wild-type recipients. CONCLUSIONS: Our results demonstrate that c-Rel is essential for robust rejection of islet allografts and support the idea that strategies that impair c-Rel function may be of value for constraining alloimmunity and facilitating survival of allogafts.
Animals↗
v-rel induces expression of three avian immunoregulatory surface receptors more efficiently than c-rel.
The c-rel gene is a member of NF-kappa B/rel family of transcription factors that regulate expression of a variety of immunoregulatory molecules. The viral oncogene, v-rel, is a truncated and mutated form of the turkey c-rel gene expressed by reticuloendotheliosis virus, strain T. In this study, we demonstrated that three avian immunoregulatory receptors, major histocompatibility (MHC) antigens class I and class II as well as the interleukin-2 receptor (IL-2R), were induced on the surface of splenic tumor cells isolated from chickens infected with reticuloendotheliosis virus, strain T. All cell lines derived from splenic tumors expressed these three proteins. Their expression also correlated with the appearance of endogenous c-rel during a graft-versus-host reaction. In vitro, both c-rel and v-rel induced MHC class I, MHC class II, and IL-2R on an avian B-lymphoid cell line, DT95, and a T-lymphoid cell line, MSB-1. Quantitative kinetic analysis demonstrated both the accumulation of MHC class II mRNA and the appearance of surface MHC class II protein in response to the synthesis of either v-rel or c-rel. We show that v-rel induced the expression of MHC class II in the avian B-cell lines DT40 and DT95 more rapidly than c-rel and that, several weeks after infection, v-rel induced MHC class II as much as 50-fold more efficiently than c-rel. Finally, in vitro infection of splenocytes with retroviruses that express v-rel or c-rel induced MHC class I, MHC class II, and IL-2R expression. Quantitative analysis confirmed that p59v-rel was consistently more efficient at inducing expression of all three immunoregulatory receptors than exogenous p68c-rel. These data suggest that during tumor development, v-rel functions to induce (or suppress) the expression of genes similarly induced (or suppressed) by c-rel. The observations reported in this study are not in agreement with a model in which v-rel promotes tumor development by functioning as a dominant negative mutant of c-rel. In contrast, these findings support the hypothesis that lymphocyte immortalization and tumor development are the result, at least in part, of the capacity of v-rel to function as a dominant positive mutant that induces expression of genes normally regulated by c-rel.
Animals↗
Expression of the oncogene of avian reticuloendotheliosis virus in Escherichia coli and identification of the transforming protein in reticuloendotheliosis virus T-transformed cells.
The genome of reticuloendotheliosis virus T (REV-T) includes a unique oncogene v-rel, which is transcribed in low amounts into a 3.0-kilobase subgenomic mRNA in REV-T-transformed lymphoid cells. To identify the v-rel protein, REV-T DNA sequences were cloned into bacterial plasmid vectors designed to achieve expression of foreign DNA sequences in Escherichia coli. Portions of the v-rel gene were joined to the 5' segment of the trpE gene. Upon induction of trpE with indoleacrylic acid, large amounts of trpE-v-rel fusion proteins were produced by the bacteria carrying these recombinant plasmids. Two trpE-v-rel fusion proteins were synthesized in E. coli, which collectively represent three-quarters of the predicted v-rel protein. Polyclonal antisera were generated to trpE-v-red fusion proteins. These antisera were used in immunoblotting experiments to identify a 57-kDa v-rel protein in REV-T-transformed lymphoid cells lines and REV-T-infected chicken embryo fibroblast cultures. The v-rel gene expressed in E. coli under lac control was found to produce a 56-kDa protein. Although REV-T-transformed and Marek disease virus-transformed lymphoid cells contain c-rel mRNA transcripts, a c-rel protein could not be detected with antisera directed against v-rel fusion proteins.
Animals↗
Origins of immunity: Relish, a compound Rel-like gene in the antibacterial defense of Drosophila.
NF-kappa B/Rel transcription factors are central regulators of mammalian immunity and are also implicated in the induction of cecropins and other antibacterial peptides in insects. We identified the gene for Relish, a compound Drosophila protein that, like mammalian p105 and p100, contains both a Rel homology domain and an I kappa B-like domain. Relish is strongly induced in infected flies, and it can activate transcription from the Cecropin A1 promoter. A Relish transcript is also detected in early embryos, suggesting that it acts in both immunity and embryogenesis. The presence of a compound Rel protein in Drosophila indicates that similar proteins were likely present in primordial immune systems and may serve unique signaling functions.
Amino Acid Sequence↗
The v-rel oncogene encodes a cell-specific transcriptional activator of certain promoters.
Transformation by the v-rel oncogene of avian reticuloendotheliosis virus strain T (Rev-T) is primarily cell-specific. While v-rel efficiently transforms chicken spleen and bone marrow stem cells in vitro and induces rapid lethal lymphomas in young birds, it does not rapidly transform chicken embryo fibroblasts. The nuclear localization of the v-rel gene product in non-transformed fibroblasts along with its ability to function as a transforming protein in the nucleus of chicken spleen cells suggests that p59v-rel might belong to the family of nuclear oncoproteins and thus may express an immortalizing function in fibroblasts. To gain insight into the specificity of cell transformation by the v-rel oncogene, we determined whether v-rel could immortalize primary rat fibroblasts. Our experiments have shown that, unlike other nuclear oncoproteins, p59v-rel did not immortalize primary rat embryo fibroblasts. However p59v-rel was able to cooperate in a synergistic way with the polyomavirus middle T protein in inducing efficient transformation of established rat fibroblasts by increasing the steady-state level of middle T RNA, indicating that p59v-rel might function as a transactivator. Cotransfection of cells from different species with the v-rel gene along with constructs expressing the chloramphenicol acetyl transferase gene under the control of different promoters revealed that p59v-rel is a cell-specific transcriptional transactivator of certain promoters. Moreover, the extent of cell-specific transactivation by v-rel correlated with its toxic effect in these same cells.
Animals↗
Stringent control of intracellular proteolysis in Escherichia coli.
Regulation of intracellular proteolysis has been compared during amino acid deficiencies in seven double auxotrophs of Escherichia coli 9723f with a common phenylalanine requirement. Individual deficiencies were either more effective than, less effective, or equal to phenylalanine deficiency in stimulating intracellular proteolysis. For each amino acid, the same relationship prevailed in inhibiting uracil incorporation into nucleic acids, a reaction series regulated by the rel gene for stringent control. The three amino acids least abundant in the cellular protein were the least effective regulators. These findings are interpreted as supportive evidence for stringent control of intracellular proteolysis by the rel gene.
Amino Acids↗
Effect of the "RNA control" locus in Escherichia coli on RNA bacteriophage R23 replication.
The effect of the rel gene of Escherichia coli on the RNA synthesis induced by phage R23 was studied. This RNA phage has the property of inhibiting ribosomal RNA formation and completely dominating the RNA synthesis of the host. Phage-specific RNA formation was found to be dependent on the allelic state of the rel gene. Determinations of RNA synthesis were made by both cumulative and short-term incorporations of uracil and adenine. Variations in labeling of nucleotide pools were compensated for by determining specific activities of ATP and UTP and using these values to obtain true, relative rates of RNA synthesis.
Adenine↗