Transcriptional Regulation by the Acetylation of Nonhistone Proteins in Humans – A New Target for Therapeutics

Das, Chandrima; Kundu, Tapas K.

doi:10.1080/15216540500090629

Cited by 70 publications

(47 citation statements)

References 54 publications

(64 reference statements)

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“…The HIF-1␣ gene promoter contains putative binding sites for several transcription factors, including Sp1, AP-1, and NF-B (23)(24)(25). Treatment of A11 cells with mithramycin A resulted in a marked suppression of HIF-1␣ mRNA expression in A11 cells, whereas sulfasarazine and curcumin showed no effect, suggesting the importance of Sp1 for the promoter activity.…”

Section: Discussionmentioning

confidence: 98%

Reactive Oxygen Species-generating Mitochondrial DNA Mutation Up-regulates Hypoxia-inducible Factor-1α Gene Transcription via Phosphatidylinositol 3-Kinase-Akt/Protein Kinase C/Histone Deacetylase Pathway

Koshikawa

Hayashi

Nakagawara

et al. 2009

Journal of Biological Chemistry

133

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Lewis lung carcinoma-derived high metastatic A11 cells constitutively overexpress hypoxia-inducible factor (HIF)-1␣ mRNA compared with low metastatic P29 cells. Because A11 cells exclusively possess a G13997A mutation in the mitochondrial NADH dehydrogenase subunit 6 (ND6) gene, we addressed here a causal relationship between the ND6 mutation and the activation of HIF-1␣ transcription, and we investigated the potential mechanism. Using trans-mitochondrial cybrids between A11 and P29 cells, we found that the ND6 mutation was directly involved in HIF-1␣ mRNA overexpression. Stimulation of HIF-1␣ transcription by the ND6 mutation was mediated by overproduction of reactive oxygen species (ROS) and subsequent activation of phosphatidylinositol 3-kinase (PI3K)-Akt and protein kinase C (PKC) signaling pathways. The up-regulation of HIF-1␣ transcription was abolished by mithramycin A, an Sp1 inhibitor, but luciferase reporter and chromatin immunoprecipitation assays indicated that Sp1 was necessary but not sufficient for HIF-1␣ mRNA overexpression in A11 cells. On the other hand, trichostatin A, a histone deacetylase (HDAC) inhibitor, markedly suppressed HIF-1␣ transcription in A11 cells. In accordance with this, HDAC activity was high in A11 cells but low in P29 cells and in A11 cells treated with the ROS scavenger ebselene, the PI3K inhibitor LY294002, and the PKC inhibitor Ro31-8220. These results suggest that the ROS-generating ND6 mutation increases HIF-1␣ transcription via the PI3K-Akt/ PKC/HDAC pathway, leading to HIF-1␣ protein accumulation in hypoxic tumor cells.

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Section: Discussionmentioning

confidence: 98%

Reactive Oxygen Species-generating Mitochondrial DNA Mutation Up-regulates Hypoxia-inducible Factor-1α Gene Transcription via Phosphatidylinositol 3-Kinase-Akt/Protein Kinase C/Histone Deacetylase Pathway

Koshikawa

Hayashi

Nakagawara

et al. 2009

Journal of Biological Chemistry

133

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“…Similarly, corepressor complexes include proteins that have deacetylase activity (6). Until now, more than 40 transcription factors and 30 other proteins are acetylated on lysine residues, and their function is thereby regulated (7)(8)(9)(10)(11)(12)(13). Depending on the functional domain that is modified, acetylation can regulate different functions of these nonhistone proteins, such as DNA recognition, protein stability, protein-protein interaction, and subcellular localization (14).…”

Section: Introductionmentioning

confidence: 99%

Epigallocatechin-3-Gallate, a Histone Acetyltransferase Inhibitor, Inhibits EBV-Induced B Lymphocyte Transformation via Suppression of RelA Acetylation

Choi¹,

Jung²,

et al. 2009

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Because the p300/CBP-mediated hyperacetylation of RelA (p65) is critical for nuclear factor-KB (NF-KB) activation, the attenuation of p65 acetylation is a potential molecular target for the prevention of chronic inflammation. During our ongoing screening study to identify natural compounds with histone acetyltransferase inhibitor (HATi) activity, we identified epigallocatechin-3-gallate (EGCG) as a novel HATi with global specificity for the majority of HAT enzymes but with no activity toward epigenetic enzymes including HDAC, SIRT1, and HMTase. At a dose of 100 Mmol/L, EGCG abrogates p300-induced p65 acetylation in vitro and in vivo, increases the level of cytosolic IKBA, and suppresses tumor necrosis factor A (TNFA)-induced NF-KB activation. We also showed that EGCG prevents TNFA-induced p65 translocation to the nucleus, confirming that hyperacetylation is critical for NF-KB translocation as well as activity. Furthermore, EGCG treatment inhibited the acetylation of p65 and the expression of NF-KB target genes in response to diverse stimuli. Finally, EGCG reduced the binding of p300 to the promoter region of interleukin-6 gene with an increased recruitment of HDAC3, which highlights the importance of the balance between HATs and histone deacetylases in the NF-KB-mediated inflammatory signaling pathway. Importantly, EGCG at 50 Mmol/L dose completely blocks EBV infection-induced cytokine expression and subsequently the EBV-induced B lymphocyte transformation. These results show the crucial role of acetylation in the development of inflammatory-related diseases. [Cancer Res 2009;69(2):583-92]

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“…Then the ES for each set was calculated by treating each as predefined peptide sets. Finally, 1 The abbreviations used are: KAT, Lysine (K)-Acetyl-Transferase; ASEB, Acetylation Set Enrichment Based; DDB1, DNA damage-binding protein 1; ES, Enrichment score; GCN5, General control of amino acid synthesis protein 5-like 2; GSEA, Gene Set Enrichment Analysis; MBD1, methyl-CpG-binding domain protein 1; MEC-17, Alpha-tubulin N-acetyltransferase; MTA1, metastasis-associated protein; MYST, MOZ, YBF2/SAS3, SAS2, and TIP60 protein; p300, E1A-associated protein p300; PCAF, p300/CBP-associated factor; WRN, Werner syndrome ATP-dependent helicase; p query , the query peptide; S b , background peptides set; S k , KAT special peptides set; S null , randomly generated peptides set. these 10,000 ES (ES(S null1 ), ES(S null2 ),..ES null9999 , plus ES(S k )) were ranked from high to low.…”

Section: Methodsmentioning

confidence: 99%

“…In order to function properly, natural proteins suffer from various post-translational modifications, among which acetylation plays critical roles in protein stability, gene expression regulation, protein-protein interactions, and cellular metabolism (1)(2)(3)(4)(5). Acetylation occurs mainly on lysine residues and has been extensively studied on histone Nterminal lysine (6,7).…”

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confidence: 99%

Characterization and Prediction of Lysine (K)-Acetyl-Transferase Specific Acetylation Sites

Wang

et al. 2012

Molecular & Cellular Proteomics

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Lysine acetylation is a well-studied post-translational modification on both histone and nonhistone proteins. More than 2000 acetylated proteins and 4000 lysine acetylation sites have been identified by large scale mass spectrometry or traditional experimental methods. Although over 20 lysine (K)-acetyl-transferases (KATs) have been characterized, which KAT is responsible for a given protein or lysine site acetylation is mostly unknown. In this work, we collected KAT-specific acetylation sites manually and analyzed sequence features surrounding the acetylated lysine of substrates from three main KAT families (CBP/p300, GCN5/PCAF, and the MYST family). We found that each of the three KAT families acetylates lysines with different sequence features. Based on these differences, we developed a computer program, Acetylation Set Enrichment Based method to predict which KATfamilies are responsible for acetylation of a given protein or lysine site. Finally, we evaluated the efficiency of our method, and experimentally detected four proteins that were predicted to be acetylated by two KAT families when one representative member of the KAT family is over expressed. We conclude that our approach, combined with more traditional experimental methods, may be useful for identifying KAT families responsible for acetylated substrates proteome-wide.

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Transcriptional Regulation by the Acetylation of Nonhistone Proteins in Humans – A New Target for Therapeutics

Cited by 70 publications

References 54 publications

Reactive Oxygen Species-generating Mitochondrial DNA Mutation Up-regulates Hypoxia-inducible Factor-1α Gene Transcription via Phosphatidylinositol 3-Kinase-Akt/Protein Kinase C/Histone Deacetylase Pathway

Reactive Oxygen Species-generating Mitochondrial DNA Mutation Up-regulates Hypoxia-inducible Factor-1α Gene Transcription via Phosphatidylinositol 3-Kinase-Akt/Protein Kinase C/Histone Deacetylase Pathway

Epigallocatechin-3-Gallate, a Histone Acetyltransferase Inhibitor, Inhibits EBV-Induced B Lymphocyte Transformation via Suppression of RelA Acetylation

Characterization and Prediction of Lysine (K)-Acetyl-Transferase Specific Acetylation Sites

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