c-rel activates but v-rel suppresses transcription from kappa B sites.

Inoue, Jun‐ichiro; Kerr, Lawrence D.; Ransone, Lynn J.; Bengal, Eyal; Hunter, Tony; Verma, Inder M.

doi:10.1073/pnas.88.9.3715

Cited by 135 publications

(123 citation statements)

References 44 publications

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“…When this sequence was disrupted by certain mutations, the transforming and transcriptional repressing abilities of v-Rel were impaired and c-Rel showed reduced cytoplasmic retention in CEF. suggested that the oncogenicity of v-Rel is based on its ability to repress promoters containing NF-KB binding sites, either through DNA binding or protein-protein interactions (3,14,15,22,33 Our results suggest that the phosphorylation of Ser-275 could have an inhibitory effect on transformation by v-Rel. Consistent with this suggestion, Ser-275 does not appear to be a major phosphorylation site in vivo in v-Rel in transformed spleen cells, even in the presence of okadaic acid (Fig.…”

Section: Discussionmentioning

confidence: 70%

A protein kinase-A recognition sequence is structurally linked to transformation by p59v-rel and cytoplasmic retention of p68c-rel.

Mosialos¹,

Hamer²,

Capobianco³

et al. 1991

Mol. Cell. Biol.

107

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The Rel family of proteins includes a number of proteins involved in transcriptional control, such as the retroviral oncoprotein v-Rel, c-Rel, the Drosophila melanogaster developmental protein Dorsal, and subunits of the transcription factor NF-KB. These proteins are related through a highly conserved domain of approximately 300 amino acids, called the Rel homology domain, that contains dimerization, DNA binding, and nuclear targeting functions. Also within the Rel homology domain, there is a conserved consensus sequence (Arg-Arg-Pro-Ser) for phosphorylation by cyclic AMP-dependent protein kinase (PKA). We used Ilnker insertion mutagenesis and site-directed mutagenesis to determine the importance of this sequence In addition, they suggest that phosphorylation at the conserved PKA site could have a negative effect on transformation and transcriptional repression by v-Rel and induce the nuclear localization of c-Rel.

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Section: Discussionmentioning

confidence: 70%

A protein kinase-A recognition sequence is structurally linked to transformation by p59v-rel and cytoplasmic retention of p68c-rel.

Mosialos¹,

Hamer²,

Capobianco³

et al. 1991

Mol. Cell. Biol.

107

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“…Similar transfection studies with p50 have failed to demonstrate transcriptional activation functions (7,57,60,64). Other studies have demonstrated that both c-rel and dorsal have activation domains within the C-terminal region (12,20,26,29,30,57). In contrast, by using an in vitro transcription assay, it has been shown that the rel homology domain of p50 is capable of transcriptional activation (19,39).…”

mentioning

confidence: 88%

Conservation of transcriptional activation functions of the NF-kappa B p50 and p65 subunits in mammalian cells and Saccharomyces cerevisiae.

Moore¹,

Ruben²,

Rosen³

1993

Mol. Cell. Biol.

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The NF-KB transcription factor complex is composed of a 50-kDa (p50) and a 65-kDa (p65) subunit. Both subunits bind to similar DNA motifs and elicit transcriptional activation as either homo-or heterodimers. By using chimeric proteins that contain the DNA binding domain of the yeast transcriptional activator GALA and subdomains of p65, three distinct transcriptional activation domains were identified. One domain was localized to a region of 42 amino acids containing a potential leucine zipper structure, consistent with earlier reports. Two other domains, both acidic and rich in prolines, were also identified. Of perhaps more significance, the same minimal activation domains that were functional in mammalian cells were also functional in the yeast Saccharomyces cerevisiae. Coexpression of the NF-KcB inhibitory molecule, IKB, reduced the transcriptional activity of p65 significantly, suggesting the ability of IKB to function in a similar manner in S. cerevisiae. Surprisingly, while the conserved rel homology domain of p65 demonstrated no transcriptional activity in either mammalian cells or S. cerevisiae, the corresponding domain in p50 was a strong transcriptional activator in S. cerevisiae. The observation that similar domains elicit transcriptional activation in mammalian cells and S. cerevisiae demonstrates strong conservation of the transcriptional machinery required for NF-cB function and provides a powerful genetic system to study the transcriptional mechanisms of these proteins.Nuclear factor KB (NF-KB), originally described as a factor involved in tissue-specific control of the mouse K light-chain enhancer (65,66), is now known to be involved in the inducible expression of a wide range of genes (2, 6, 44). The KB DNA binding site has been identified in the regulatory elements of cytokine, cytokine receptor, major histocompatibility complex class I and II antigens, inflammatory and acute-phase response genes, and several viral enhancer elements (2, 6, 44). DNA binding activity appears to be constitutive in mature B cells (66) and in activated macrophages (24). However, in most other cells NF-KB is complexed with an inhibitory molecule (IKB) in the cytoplasm (3,4,21). Sequestration in the cytoplasm is thought to involve masking of the nuclear localization signal (8). Upon activation by a variety of stimuli, including mitogens, cytokines, and various viral proteins (2, 6, 44), NF-KB shuttles to the nucleus, a process thought to involve phosphorylation of IKB (21,68). Initial studies demonstrated that IKB inhibits binding of the p65 homodimer and the p5O/p65 heterodimer through interaction with p65 (5, 21, 54, 78). However, recent studies suggest that both subunits can interact with IKB (8).Biochemical studies have shown that the major form of NF-KB is composed of a heterodimer of a 50-kDa (p50) and a 65-kDa (p65) subunit (5). Both subunits of NF-KB have been cloned, and sequence analyses demonstrate strong similarity in the amino-terminal 300 amino acids to the rel proto-oncogene product (22,38,54,58), origi...

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“…For example, because v-Rel is a relatively weak activator of transcription, high-level expression of v-Rel reduces transcription from kB site-containing promoters in cells that have constitutively nuclear kB-site activating complexes (Inoue et al, 1991;Ishikawa et al, 1993;McDonnell et al, 1992;Richardson and Gilmore, 1991;Walker et al, 1992). That is, v-Rel homodimers displace more strongly activating complexes, such as ones containing RelA or c-Rel, and reduce the level of transcription.…”

Section: Dna Binding By V-relmentioning

confidence: 99%

“…Moreover, because v-Rel can form heterodimers with endogenous Rel proteins and transcriptionally activate their genes, the analysis of e ects of v-Rel on kB site-containing promoters can become somewhat muddled in vertebrate cells. Therefore, many experiments that have investigated transcriptional activation of kB site promoters by v-Rel have been performed in cell types that lack endogenous Rel proteins, such as in yeast, Drosophila cells, mouse F9 teratocarcinoma cells or human Tera-2 embryonal carcinoma cells, all of which lack endogenous kB sitebinding activity Inoue et al, 1991;Ishikawa et al, 1993;Kamens and Brent, 1991;Mosialos and Gilmore, 1993;Sachdev et al, 1997).…”

Section: Dna Binding By V-relmentioning

confidence: 99%

Multiple mutations contribute to the oncogenicity of the retroviral oncoprotein v-Rel

1999

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The avian Rev-T retrovirus encodes the v-Rel oncoprotein, which is a member of the Rel/NF-kB transcription factor family. v-Rel induces a rapidly fatal lymphoma/ leukemia in young birds, and v-Rel can transform and immortalize a variety of avian cell types in vitro. Although Rel/NF-kB transcription factors have been associated with oncogenesis in mammals, v-Rel is the only member of this family that is frankly oncogenic in animal model systems. The potent oncogenicity of v-Rel is the consequence of a number of mutations that have altered its activity and regulation: for example, certain mutations decrease its ability to be regulated by IkBa, change its DNA-binding site speci®city, and endow it with new transactivation properties. The study of v-Rel will continue to increase our knowledge of how cellular Rel proteins contribute to oncogenesis by a ecting cell growth, altering cell-cycle regulation, and blocking apoptosis. This review will discuss biological and molecular activities of v-Rel, with particular attention to how these activities relate to structure ± function aspects of the Rel/NF-kB transcription factors.

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c-rel activates but v-rel suppresses transcription from kappa B sites.

Cited by 135 publications

References 44 publications

A protein kinase-A recognition sequence is structurally linked to transformation by p59v-rel and cytoplasmic retention of p68c-rel.

A protein kinase-A recognition sequence is structurally linked to transformation by p59v-rel and cytoplasmic retention of p68c-rel.

Conservation of transcriptional activation functions of the NF-kappa B p50 and p65 subunits in mammalian cells and Saccharomyces cerevisiae.

Multiple mutations contribute to the oncogenicity of the retroviral oncoprotein v-Rel

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