Proper expression of the Gcn5 histone acetyltransferase is required for neural tube closure in mouse embryos

Lin, Wenchu; Zhang, Zhijing; Srajer, Geraldine; Chen, Yi Chun; Huang, Maosheng; Phan, Huy; Dent, Sharon Y.R.

doi:10.1002/dvdy.21479

Cited by 58 publications

(58 citation statements)

References 63 publications

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“…Recent reports by several groups, including ours (18,30,32), have demonstrated regulation of the GLI proteins by Hedgehog and non-Hedgehog signaling in multiple cancer types. Here, we provide evidence that the transcription factor GLI3 is a novel effector of the KRAS-PI3K-AKT1 pathway in cancer cells.…”

Section: Discussionmentioning

confidence: 92%

“…Here, we tested whether activation by GLI3 involved histone acetyltransferases, molecules that have been shown to cooperate with GLI proteins during development (31,32). RNAi knockdown using two independent shRNAs or a pooled of shRNAs targeting the acetyltransferase p300 led to a decrease in VMP1 expression (Fig.…”

Section: Kras-gli3 Pathway Couples Membrane Signals To Transcriptionamentioning

confidence: 99%

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Novel AKT1-GLI3-VMP1 Pathway Mediates KRAS Oncogene-induced Autophagy in Cancer Cells

Ré

Fernández‐Barrena

Almada

et al. 2012

Journal of Biological Chemistry

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Background: Autophagy plays a role in cancer development. Results: Oncogenic KRAS induces Vacuole Membrane Protein 1 (VMP1) through a novel AKT1-GLI3-p300 pathway and requires VMP1 to regulate autophagy in cancer cells. Conclusion: Define a novel pathway initiated by the oncogene KRAS regulating autophagy. Significance: These findings contribute to the understanding of the mechanism underlying oncogene-induced autophagy.

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Section: Discussionmentioning

confidence: 92%

Section: Kras-gli3 Pathway Couples Membrane Signals To Transcriptionamentioning

confidence: 99%

Novel AKT1-GLI3-VMP1 Pathway Mediates KRAS Oncogene-induced Autophagy in Cancer Cells

Ré

Fernández‐Barrena

Almada

et al. 2012

Journal of Biological Chemistry

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“…Before sacrifice, glycemia was measured by tail-bleeding using an Ascensia Elite Blood Glucose Meter (Bayer). The generation of the Gcn5 flox allele was previously described (31). To generate liver-specific deletion of Gcn5, Gcn5 flox/flox (Gcn5 f/f ) mice were crossed with Gcn5 flox/ϩ ; albumin-Cre ϩ/Ϫ mice.…”

Section: Animal Experimentsmentioning

confidence: 99%

“…To generate liver-specific deletion of Gcn5, Gcn5 flox/flox (Gcn5 f/f ) mice were crossed with Gcn5 flox/ϩ ; albumin-Cre ϩ/Ϫ mice. Homozygous Gcn5 f/f animals were identified using primers described in Lin et al (31). Animal experiments were conducted in accordance with the Dana-Farber Cancer Institute Institutional Animal Care and Use Committee.…”

Section: Animal Experimentsmentioning

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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“…Among the other families of HATs, the role of Gcn5 in neural development has also been documented, as the acetyltransferase activity and sufficient expression of this enzyme are required for neural tube closure in mice [55,56]. Surprisingly, while p300 HAT mutants exhibit defects in multiple organ systems, the effects of mutating Gcn5 are restricted to the neural tissue, implicating the specificity of Gcn5 acetyltransferase activity, with potential redundancy with PCAF in other tissues [55].…”

Section: Hats During Neural Developmentmentioning

confidence: 99%

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

et al. 2013

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The acetylation of histone and non-histone proteins controls a great deal of cellular functions, thereby affecting the entire organism, including the brain. Acetylation modifications are mediated through histone acetyltransferases (HAT) and deacetylases (HDAC), and the balance of these enzymes regulates neuronal homeostasis, maintaining the pre-existing acetyl marks responsible for the global chromatin structure, as well as regulating specific dynamic acetyl marks that respond to changes and facilitate neurons to encode and strengthen longterm events in the brain circuitry (e.g., memory formation). Unfortunately, the dysfunction of these finely-tuned regulations might lead to pathological conditions, and the deregulation of the HAT/HDAC balance has been implicated in neurological disorders. During the last decade, research has focused on HDAC inhibitors that induce a histone hyperacetylated state to compensate acetylation deficits. The use of these inhibitors as a therapeutic option was efficient in several animal models of neurological disorders. The elaboration of new cell-permeant HAT activators opens a new era of research on acetylation regulation. Although pathological animal models have not been tested yet, HAT activator molecules have already proven to be beneficial in ameliorating brain functions associated with learning and memory, and adult neurogenesis in wild-type animals. Thus, HAT activator molecules contribute to an exciting area of research.

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Proper expression of the Gcn5 histone acetyltransferase is required for neural tube closure in mouse embryos

Cited by 58 publications

References 63 publications

Novel AKT1-GLI3-VMP1 Pathway Mediates KRAS Oncogene-induced Autophagy in Cancer Cells

Novel AKT1-GLI3-VMP1 Pathway Mediates KRAS Oncogene-induced Autophagy in Cancer Cells

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

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

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