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Quantitative phosphoproteomic analysis of early alterations in protein phosphorylation by 2,3,7,8-tetrachlorodibenzo-p-dioxin.
J. Proteome Res. 12, 866-882 (2013)
A comprehensive quantitative analysis of changes in protein phosphorylation preceding or accompanying transcriptional activation by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in 5L rat hepatoma cells was performed using the SILAC approach. Following exposure of the cells to DMSO or 1 nM TCDD for 0.5 to 2 h, 5648 phosphorylated peptides corresponding to 2156 phosphoproteins were identified. Eight peptides exhibited a statistically significantly altered phosphorylation because of TCDD exposure and 22 showed a regulation factor of ≥1.5 in one of the experiments per time point. The vast majority of the TCCD-induced phosphorylation changes had not been reported before. The transcription factor ARNT, the obligate partner for gene activation by the TCDD-bound Ah receptor, exhibited an up-regulation of its Ser77 phosphorylation, a modification known to control the differential binding of ARNT homodimers and heterodimers to different enhancers suggesting that this phosphorylation represents a novel mechanism contributing to the alteration of gene expression by TCDD. Other proteins with altered phosphorylation included, among others, various transcriptional coregulators previously unknown to participate in TCDD-induced gene activation, regulators of small GTPases of the Ras superfamily, UBX domain-containing proteins and the oncogenic protein LYRIC. The results open up new directions for research on the molecular mechanisms of dioxin action and toxicity.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
TCDD; dioxin; protein phosphorylation; phosphoproteomics; SILAC; SIMAC; ARNT; transcriptional regulation; GTPases; 5L cells; Aryl-hydrocarbon Receptor ; Rat Hepatoma-cells ; Nucleotide Exchange Factor ; Ah Dioxin Receptor ; Nongenomic Pathway ; Mass-spectrometry ; Calcium-channel ; Gene-expression ; Cyclooxygenase-2 Expression ; Transcriptional Induction
ISSN (print) / ISBN
1535-3893
e-ISSN
1535-3907
Journal
Journal of Proteome Research
Quellenangaben
Volume: 12,
Issue: 2,
Pages: 866-882
Publisher
American Chemical Society (ACS)
Non-patent literature
Publications
Reviewing status
Peer reviewed