Two distinct yeast transcriptional activators require the function of the GCN5 protein to promote normal levels of transcription.

Georgakopoulos, Tassos; Thireos, George

doi:10.1002/j.1460-2075.1992.tb05507.x

Cited by 288 publications

(212 citation statements)

References 59 publications

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“…It is thought that this functional interaction is mediated by the transcriptional coactivators. Gcn5p (Ada4p) is a component of a multimeric transcription coactivator complex SAGA that is composed of Ada1p, Ada2p, Ada3p, Ada5p/Spt20p, Spt3, and Spt7 (Georgakopoulos and Thireos 1992;Marcus et al 1994;Horiuchi et al 1995;Marcus et al 1996;Grant et al 1997). Gcn5p is an acetyltransferase that facilitates transcription by acetylating histone to relax chromatin structures (Brownell et al 1996).…”

Section: Additional Modifiers Of the Upr: Saga And Ptc2mentioning

confidence: 99%

Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls

Kaufman¹

1999

Genes & Development

2,092

1,745

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Section: Additional Modifiers Of the Upr: Saga And Ptc2mentioning

confidence: 99%

Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls

Kaufman¹

1999

Genes & Development

2,092

1,745

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“…Thus, there is the alternative possibility that other proteins in the acetyltransferase complexes could undergo post-translational modification to alter the complex composition and increase GCN5 activity, as has been described earlier (38). GCN5 is highly conserved across species (39) and was originally identified in yeast as an essential component for proper activation of the transcriptional response to amino acid starvation mediated by GCN4 (40). It was recently shown in lower organisms that amino acids can activate acetyltransferase activity of GCN5-related N-acetyltransferase (GNAT) protein (41).…”

Section: Methionine Regulates Pgc-1␣ Activitymentioning

confidence: 99%

The Methionine Transamination Pathway Controls Hepatic Glucose Metabolism through Regulation of the GCN5 Acetyltransferase and the PGC-1α Transcriptional Coactivator

Tavares

Sharabi

Dominy

et al. 2016

Journal of Biological Chemistry

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Methionine is an essential sulfur amino acid that is engaged in key cellular functions such as protein synthesis and is a precursor for critical metabolites involved in maintaining cellular homeostasis. In mammals, in response to nutrient conditions, the liver plays a significant role in regulating methionine concentrations by altering its flux through the transmethylation, transsulfuration, and transamination metabolic pathways. A comprehensive understanding of how hepatic methionine metabolism intersects with other regulatory nutrient signaling and transcriptional events is, however, lacking. Here, we show that methionine and derived-sulfur metabolites in the transamination pathway activate the GCN5 acetyltransferase promoting acetylation of the transcriptional coactivator PGC-1␣ to control hepatic gluconeogenesis. Methionine was the only essential amino acid that rapidly induced PGC-1␣ acetylation through activating the GCN5 acetyltransferase. Experiments employing metabolic pathway intermediates revealed that methionine transamination, and not the transmethylation or transsulfuration pathways, contributed to methionine-induced PGC-1␣ acetylation. Moreover, aminooxyacetic acid, a transaminase inhibitor, was able to potently suppress PGC-1␣ acetylation stimulated by methionine, which was accompanied by predicted alterations in PGC-1␣-mediated gluconeogenic gene expression and glucose production in primary murine hepatocytes. Methionine administration in mice likewise induced hepatic PGC-1␣ acetylation, suppressed the gluconeogenic gene program, and lowered glycemia, indicating that a similar phenomenon occurs in vivo. These results highlight a communication between methionine metabolism and PGC-1␣-mediated hepatic gluconeogenesis, suggesting that influencing methionine metabolic flux has the potential to be therapeutically exploited for diabetes treatment.Amino acid sensing is a critical mechanism that cells employ to maintain homeostasis and enable survival upon fluctuations in the nutritional environment (1, 2). Despite variability in side chain chemical structure, cells are able to distinguish the distinct amino acids through the use of specific tRNAs. The amino acid protein sensor GCN2 detects deficiencies in amino acids in a tRNA-dependent manner and reprograms cellular metabolism to modulate energy consumption and maintain homeostasis (3, 4). Although mTORC1 is not considered to be a direct sensor of amino acid levels, it functions similarly to GCN2 to alter metabolic pathways in response to amino acid deprivation (5). Methionine, a dietary essential amino acid, is among the more toxic of the L-amino acids, and hence its abundance needs to be precisely regulated (6, 7). The liver is the primary organ concerned with the detoxification of methionine, and hence its ability to sense alterations in concentrations of this amino acid is vital (8). The existence of any cross-talk between hepatic methionine metabolism and other nutrient-regulated metabolic processes in the liver, such as glucose production, requi...

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“…Mutations within four ADA genes, ADA2, NGG1/ADA3, GCN5/ADA4, and ADA5, suppress the toxicity of VP16 by inhibiting its ability to activate transcription (11,12). These genes are also required for transactivation by GCN4p (11)(12)(13); in fact, GCN5p had been identified because it is required for maximal activation by GCN4p (14). Genetic and in vitro biochemical evidence suggests that the ADA proteins likely act in a complex that contains at least ADA2p, NGG1p, GCN5p, and ADA5p (10 -13, 15-18).…”

mentioning

confidence: 99%

Identification of Native Complexes Containing the Yeast Coactivator/Repressor Proteins NGG1/ADA3 and ADA2

Saleh

Lang

Cook

et al. 1997

Journal of Biological Chemistry

109

119

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NGG1p/ADA3p and ADA2p are dual function regulators that stimulate or inhibit a set of yeast transcriptional activator proteins. In vitro, NGG1p and ADA2p associate in a complex that also contains GCN5p (Horiuchi, J., Silverman, N., Marcus, G. A., and Guarente, L. (1995) Mol. Cell. Biol. 15, 1203-1209). We have found that NGG1p and ADA2p are coimmunoprecipitated from yeast whole cell extracts. In fact, <2% of cellular ADA2p was not associated with NGG1p. Also in agreement with their association in vivo, the stability of ADA2p and NGG1p depended on the presence of each other. In addition, three NGG1p-and ADA2p-containing peak fractions were resolved by Q-Sepharose Fast Flow ion-exchange chromatography of whole cell extract. The presence of another high molecular mass complex was supported by the separation of one of the NGG1p-and ADA2p-containing peak fractions by gel-filtration chromatography. Together, the combination of ion-exchange and gel-filtration chromatography suggests a total of four complexes, two with sizes of >2 MDa and single complexes of ϳ900 and 200 kDa. At least one of these complexes was found to associate with the TATA-binding protein (TBP) since TBP was present in immunoprecipitates with NGG1p. The association of TBP with the ADA proteins required amino acids 274 -307 of NGG1p, a region of NGG1p required for activity. This supports a role for NGG1p in the interaction with TBP and suggests that the interaction with TBP is functionally relevant.Activated transcription by RNA polymerase II requires the action of the basal transcriptional machinery, sequence-specific activator proteins, and coactivator or mediator proteins (1). Coactivators positively influence activator function either by providing a regulatory interface between the basal machinery and the activator protein or by enabling these components to contend with a DNA template in the form of chromatin. Coactivators have generally been found as components of regulatory complexes. The TBP 1 ⅐TBP-associated factor complex, the RNA polymerase II holoenzyme complex, and the Swi⅐Snf complex represent principal examples (reviewed in Refs. 2-4). The mechanisms and component structure of these complexes may overlap as suggested by the finding of Swi/Snf components (5) within the RNA polymerase II holoenzyme (6), the TBP-associated factor complex, and transcription factor IIF (7).Probably through related mechanisms, coactivator complexes can also be involved in repression. We initially discovered NGG1 based on its requirement for full inhibition of the GAL4 activator protein in glucose media (8). NGG1p likely acts as a more general repressor because transcriptional activation by the carboxyl-terminal activation domain of PDR1p is enhanced in a ngg1 background (9). Guarente and co-workers (10) independently isolated NGG1/ADA3 based on suppression of the toxicity of overexpression of VP16 in yeast. Mutations within four ADA genes, ADA2, NGG1/ADA3, GCN5/ADA4, and ADA5, suppress the toxicity of VP16 by inhibiting its ability to activate transcription (...

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Two distinct yeast transcriptional activators require the function of the GCN5 protein to promote normal levels of transcription.

Cited by 288 publications

References 59 publications

Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls

Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls

The Methionine Transamination Pathway Controls Hepatic Glucose Metabolism through Regulation of the GCN5 Acetyltransferase and the PGC-1α Transcriptional Coactivator

Identification of Native Complexes Containing the Yeast Coactivator/Repressor Proteins NGG1/ADA3 and ADA2

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