Distinct classes of transcriptional activating domains function by different mechanisms

Tasset, Diane M.; Tora, Làszlò; Fromental, Catherine; Scheer, Elisabeth; Chambon, Pierre

doi:10.1016/0092-8674(90)90394-t

Cited by 360 publications

(286 citation statements)

References 58 publications

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“…The observations reported in Table 2 are consistent with the hypothesis that the AAM dimer, RelA, and VP16 can all interact with, and compete for, a common cellular cofactor(s), i.e., that these activation domains are mechanistically similar (29,35,46). As a more rigorous test of this hypothesis, we have taken advantage of the finding that acidic activators of the VP16 type are characterized by a high degree of dependence on the expression of ADA2, a putative transcriptional adaptor protein, for biological activity in yeast cells (3).…”

supporting

confidence: 78%

“…While TFIIB has been clearly implicated as a target for VP16, evidence also indicates that VP16 can affect initiation complex assembly at steps subsequent to TFIIB recruitment (5). Finally, squelching experiments strongly suggest that different classes of activators also require specific cofactors that do not form part of the basal transcriptional machinery (12,29,46).…”

Section: Discussionmentioning

confidence: 99%

“…Some research has suggested that activation domains may directly interact with components of the general transcriptional machinery, such as the TATA-binding protein (TBP) or the general factor TFIIB (6, 23-25, 27, 44). In contrast, the observation that overexpression of activation domains can result in the inhibition (squelching) of activated but not basal transcription has been interpreted to mean that these domains are titrating out a protein that is distinct from these general factors (2,12,29,46). Potential candidate proteins for this coactivator or adaptor role include the TBP-associated factors (TAFs) (15,21) as well as two proteins termed ADA2 and ADA3 that have been shown to be required for acidic activation domain function in the yeast Saccharomyces cerevisiae (3,34 has been the acidic class, and particularly the activation domain of the prototypic VP16 transcriptional activator encoded by herpes simplex virus (35,48,49).…”

mentioning

confidence: 99%

“…One approach to addressing this problem is based on the experimental finding that transcriptional activation domain function requires cellular adaptors or coactivators that appear to be expressed at relatively modest levels. Overexpression in trans of an activation domain that lacks a relevant target specificity domain can therefore titrate out these cofactor(s) and inhibit (squelch) the activity of transcriptional activation domains that act through the same cellular cofactors, i.e., that belong to the same class of activators (29,35,46).…”

mentioning

confidence: 99%

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Mutational analysis of the transcription activation domain of RelA: identification of a highly synergistic minimal acidic activation module.

Blair¹,

Bogerd²,

Madore³

et al. 1994

Mol. Cell. Biol.

107

124

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The potent C-terminal activation domain of the RelA(p65) subunit of the cellular transcription factor NF-KB is shown to contain several discrete acidic activation modules. These short, -11-amino-acid modules were able to give rise to only a low level of transcription activation when fused to the GAL4 DNA-binding domain as monomers. However, dimers and higher-order multimers activated the transcription of minimal promoter elements as effectively as the full-length RelA or VP16 activation domain. Therefore, this 11-aminoacid ReIA-derived acidic module appears to contain all of the sequence information required to fully activate a target promoter element as long as it is presented in a form that permits functional synergy. Critical primary sequence requirements for acidic activation module function included a core phenylalanine residue and flanking bulky hydrophobic residues. Overall negative charge was necessary but not sufficient for function. While dimeric forms of the 11-amino-acid acidic activation module bound to either TFIIB or TATA-binding protein efficiently in vitro, a similarly charged peptide lacking the core phenylalanine residue failed to interact.Overall, these data demonstrate that the biological activity of the RelA activation domain is dependent on acidic activator sequences that are closely comparable to those detected in the activation domain of the viral VP16 regulatory protein. We hypothesize that the ability of these acidic activators to specifically interact with multiple components of the transcription initiation complex likely underlies the dramatic functional synergy exhibited by this class of activation domains in vivo.

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supporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Mutational analysis of the transcription activation domain of RelA: identification of a highly synergistic minimal acidic activation module.

Blair¹,

Bogerd²,

Madore³

et al. 1994

Mol. Cell. Biol.

107

124

View full text Add to dashboard Cite

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“…The CBF5 mRNA is elevated compared to the wild type under permissive conditions, and the protein is likely to be overexpressed. We speculate that this overexpression leads to a form of squelching, a phenomenon well known from transcription studies (e.g., see Gill and Ptashne 1988;Tasset et al 1990;Flanagan et al 1991). Squelching often results from the overexpression of a free form of a component that normally functions in a complex with other proteins.…”

Section: Discussionmentioning

confidence: 99%

The box H+ACA snoRNAs carry Cbf5p, the putative rRNA pseudouridine synthase

Lafontaine¹,

Bousquet‐Antonelli²,

Henry³

et al. 1998

Genes & Development

321

324

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Many or all of the sites of pseudouridine (⌿) formation in eukaryotic rRNA are selected by site-specific base-pairing with members of the box H + ACA class of small nucleolar RNAs (snoRNAs). Database searches previously identified strong homology between the rat nucleolar protein Nap57p, its yeast homolog Cbf5p, and the Escherichia coli ⌿ synthase truB/P35. We therefore tested whether Cbf5p is required for synthesis of ⌿ in the yeast rRNA. After genetic depletion of Cbf5p, formation of ⌿ in the pre-rRNA is dramatically inhibited, resulting in accumulation of the unmodified rRNA. Protein A-tagged Cbf5p coprecipitates all tested members of the box H + ACA snoRNAs but not box C + D snoRNAs or other RNA species. Genetic depletion of Cbf5p leads to depletion of all box H + ACA snoRNAs. These include snR30, which is required for pre-rRNA processing. Depletion of Cbf5p also results in a pre-rRNA processing defect similar to that seen on depletion of snR30. We conclude that Cbf5p is likely to be the rRNA ⌿ synthase and is an integral component of the box H + ACA class of snoRNPs, which function to target the enzyme to its site of action.

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Evidence for a mechanism of demyelination by human JC virus: Negative transcriptional regulation of RNA and protein levels from myelin basic protein gene by large tumor antigen in human glioblastoma cells

et al. 1996

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Human JC virus (JCV) is a neurotropic human polyomavirus that was found in the plaques and oligodendroglial cells of the brains of patients with the fatal demyelinating disease, progressive multifocal leukoencephalopathy (PML). Transgenic mice expressing JCV large tumor (T)-antigen from integrated DNA showed dysmyelination in the central nervous system. However, the role of T-antigen from episomal DNA in the demyelination in PML remains unclear. In this report, we examined the effect of episomally expressed JCV T-antigen on the expression of myelin basic protein (MBP) in U-87 MG human glioblastoma cells to study the mechanism of demyelination. Expression assays of the MBP promoter in U-87 MG detected a 2.5-fold reduction in cells expressing intact T-antigen. Next, U-87 MG expressing T-antigen were examined by RNase protection assays for mRNA accumulation from the endogenous MBP promoter. Also, the expression of the MBP promoter plasmid was determined using in vitro transcription assays with extracts from T-antigen expressing cells. Both assays found a similar down-regulation of the MBP promoter by T-antigen, confirming that negative regulation occurred at the transcriptional level for the endogenous and exogenous MBP promoters. Furthermore, in situ immunofluorescence assays and quantitative Western blot analysis provided convincing evidence of a similar reduction in the level of MBP produced from the functional endogenous gene in U-87 MG glioblastoma cells expressing T-antigen. Thus, we provide evidence for the role of T-antigen in a transcriptional control mechanism for the demyelination that is caused by JCV in PML patients.

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Distinct classes of transcriptional activating domains function by different mechanisms

Cited by 360 publications

References 58 publications

Mutational analysis of the transcription activation domain of RelA: identification of a highly synergistic minimal acidic activation module.

Mutational analysis of the transcription activation domain of RelA: identification of a highly synergistic minimal acidic activation module.

The box H+ACA snoRNAs carry Cbf5p, the putative rRNA pseudouridine synthase

Evidence for a mechanism of demyelination by human JC virus: Negative transcriptional regulation of RNA and protein levels from myelin basic protein gene by large tumor antigen in human glioblastoma cells

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