Identification of Posttranslational Modifications in Peroxisome Proliferator-Activated Receptor<i>γ</i>Using Mass Spectrometry

Katsura, Shogo; Okumura, Tomoko; Itô, Ryo; Sugawara, Akira; Yokoyama, Atsushi

doi:10.1155/2014/468925

Cited by 9 publications

(5 citation statements)

References 29 publications

(38 reference statements)

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“…Then, coactivators, such as steroid receptor coactivators, PPARγ coactivator 1s, histone acyltransferases, and the mediator complexes, are recruited and interact with PPARγ to promote gene transcription 10 , 14 , 15 . In addition to ligands, post-translational modifications (PTMs), including phosphorylation, SUMOylation, acetylation, and ubiquitination, are considered as some of the major processes regulating the transcriptional activity of PPARγ 16 , 17 . Phosphorylation of PPARγ at Ser112 by mitogen-activated protein kinase suppresses PPARγ transcriptional activity and adipocyte differentiation 18 .…”

Section: Introductionmentioning

confidence: 99%

The E3 ubiquitin ligase TRIM25 regulates adipocyte differentiation via proteasome-mediated degradation of PPARγ

et al. 2018

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Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-dependent transcription factor that regulates adipocyte differentiation and glucose homeostasis. The transcriptional activity of PPARγ is regulated not only by ligands but also by post-translational modifications (PTMs). In this study, we demonstrate that a novel E3 ligase of PPARγ, tripartite motif-containing 25 (TRIM25), directly induced the ubiquitination of PPARγ, leading to its proteasome-dependent degradation. During adipocyte differentiation, both TRIM25 mRNA and protein expression significantly decreased and negatively correlated with the expression of PPARγ. The stable expression of TRIM25 reduced PPARγ protein levels and suppressed adipocyte differentiation in 3T3-L1 cells. In contrast, the specific knockdown of TRIM25 increased PPARγ protein levels and stimulated adipocyte differentiation. Furthermore, TRIM25-knockout mouse embryonic fibroblasts (MEFs) exhibited an increased adipocyte differentiation capability compared with wild-type MEFs. Taken together, these data indicate that TRIM25 is a novel E3 ubiquitin ligase of PPARγ and that TRIM25 is a novel target for PPARγ-associated metabolic diseases.

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Section: Introductionmentioning

confidence: 99%

The E3 ubiquitin ligase TRIM25 regulates adipocyte differentiation via proteasome-mediated degradation of PPARγ

et al. 2018

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“…The chemical ligands have been developed into therapeutic drugs for the treatment of type 2 diabetes. In addition to the ligand activation, PPARγ can also be regulated through diverse posttranslational modifications [16]. In recent years, it has been found that PPARγ serine 245 (or S273 in PPARγ isoform 2) can be phosphorylated by cyclin-dependent kinase 5 (CDK5), and this posttranslational modification is related with insulin resistance in obese individuals [17].…”

Section: Introductionmentioning

confidence: 99%

“…This finding provides a link between the regulation of AMPK and PPARγ. In the literature, CDK5 is reported to regulate posttranslational modifications of PPARγ [16]. Phosphorylation of PPARγ at serine 273 by CDK5 has been shown to stimulate diabetogenic gene expression in adipose tissues [17].…”

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confidence: 99%

Crocin Improves Insulin Sensitivity and Ameliorates Adiposity by Regulating AMPK-CDK5-PPARγ Signaling

Fang

2020

BioMed Research International

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Crocin is a carotenoid compound which possesses multiple biological activities. Our and other laboratory’s previous findings show that crocin alleviates obesity and type 2 diabetes-related complications. We have found that crocin activates AMP-activated protein kinase (AMPK) signaling and inhibition of AMPK suppresses crocin-induced protective effects. However, the causal role of AMPK activation in the biological role of crocin is still not verified. In the present study, we showed that crocin markedly inhibits the changes of glucose metabolic parameters and serum lipid profiles in wild type diabetic mice. In AMPKα KO diabetic mice, those protective effects of crocin against glucose and lipid metabolic dysfunction were abolished. These results demonstrated AMPK activation was responsible for the beneficial effects of crocin on metabolic dysfunction. Moreover, we have shown that the antiobese effect of crocin has been abolished by the deficiency of AMPKα. We also showed that crocin induced a significant decrease of CDK5 protein level in wild type diabetic mice, while this effect was abolished in AMPKα KO diabetic mice. The regulation of downstream targets of CDK5/PPARγ by crocin was abolished by the deficiency of AMPK. In conclusion, our study verified that activation of AMPK is involved in crocin-induced protective effects against glucose and lipid metabolic dysfunction. Activation of AMPK downregulates the protein level of CDK5, followed by the decrease of PPARγ phosphorylation, leading to the inhibition of adipose formation and metabolic dysfunction. Our study provides new insights into the mechanism of protective effects of crocin and interaction of AMPK and CDK5/PPARγ signaling.

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“…Given the importance of PPARγ in various physiological and pathological processes, PPARγ gene regulation has been extensively studied at the genomic and transcriptional levels in recent decades (Lee and Ge, 2014). The half-life of PPARγ mRNA and protein is short and PPARγ protein can be post-translationally modified in various ways (van Beekum et al, 2009;Katsura et al, 2014), suggesting that posttranscriptional regulation is crucial for its function. However, to date, posttranscriptional regulation by the 5 UTR has been mostly unexplored.…”

Section: Introductionmentioning

confidence: 99%

An Upstream Open Reading Frame Represses Translation of Chicken PPARγ Transcript Variant 1

Chu

Huang

et al. 2020

Front. Genet.

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Peroxisome proliferator-activated receptor γ (PPARγ) is a master regulator of adipogenesis. The PPARγ gene produces various transcripts with different 5untranslated regions (5 UTRs) because of alternative promoter usage and splicing. The 5 UTR plays important roles in posttranscriptional gene regulation. However, to date, the regulatory role and underlying mechanism of 5 UTRs in the posttranscriptional regulation of PPARγ expression remain largely unclear. In this study, we investigated the effects of 5 UTRs on posttranscriptional regulation using reporter assays. Our results showed that the five PPARγ 5 UTRs exerted different effects on reporter gene activity. Bioinformatics analysis showed that chicken PPARγ transcript 1 (PPARγ1) possessed an upstream open reading frame (uORF) in its 5 UTR. Mutation analysis showed that a mutation in the uORF led to increased Renilla luciferase activity and PPARγ protein expression, but decreased Renilla luciferase and PPARγ1 mRNA expression. mRNA stability analysis using real-time RT-PCR showed that the uORF mutation did not interfere with mRNA stability, but promoter activity analysis of the cloned 5 UTR showed that the uORF mutation reduced promoter activity. Furthermore, in vitro transcription/translation assays demonstrated that the uORF mutation markedly increased the translation of PPARγ1 mRNA. Collectively, our results indicate that the uORF represses the translation of chicken PPARγ1 mRNA.

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Identification of Posttranslational Modifications in Peroxisome Proliferator-Activated ReceptorγUsing Mass Spectrometry

Cited by 9 publications

References 29 publications

The E3 ubiquitin ligase TRIM25 regulates adipocyte differentiation via proteasome-mediated degradation of PPARγ

The E3 ubiquitin ligase TRIM25 regulates adipocyte differentiation via proteasome-mediated degradation of PPARγ

Crocin Improves Insulin Sensitivity and Ameliorates Adiposity by Regulating AMPK-CDK5-PPARγ Signaling

An Upstream Open Reading Frame Represses Translation of Chicken PPARγ Transcript Variant 1

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