Pioglitazone inhibits EGFR/MDM2 signaling-mediated PPARγ degradation

Shi, Juanjuan; Zhang, Wenbo; You, Mengli; Xü, Ying; Hou, Yongzhong; Jin, Jianhua

doi:10.1016/j.ejphar.2016.09.010

Cited by 12 publications

(5 citation statements)

References 30 publications

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“…Keshet et al 42 demonstrated that c-Abl-mediated tyrosine phosphorylation of PPARγ increases its accumulation. In addition, epidermal growth factor receptor has been suggested to induce PPARγ phosphorylation, which could lead to MDM2 E3 ubiquitin ligase-mediated PPARγ ubiquitination and degradation 43 , 44 . Thus, we tested whether known phosphorylation sites of PPARγ could modulate TRIM25-mediated PPARγ ubiquitination and degradation.…”

Section: Discussionmentioning

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: Discussionmentioning

confidence: 99%

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

et al. 2018

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“…Furthermore, Xu et al found that MDM2 binds to PPARγ and is responsible for its ubiquitin-mediated degradation, emphasizing that this process requires the involvement of EGFR (Xu et al 2016 ). Shi et al subsequently confirmed that inhibiting the EGFR/MDM2 pathway significantly curtails PPARγ degradation (Shi et al 2016 ). Notably, Hallenborg et al discovered that MDM2 indirectly modulates PPARγ expression by mediating the nuclear sequestration of transcriptional cofactors MORC2 and LIPIN1 in adipose cells (Hallenborg et al 2021 ).…”

Section: Discussionmentioning

confidence: 93%

BRD4 promotes gouty arthritis through MDM2-mediated PPARγ degradation and pyroptosis

Xu,

Qiu

2024

Mol Med

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Background Gouty arthritis (GA) is characterized by monosodium urate (MSU) crystal accumulation that instigates NLRP3-mediated pyroptosis; however, the underlying regulatory mechanisms have yet to be fully elucidated. The present research endeavors to elucidate the regulatory mechanisms underpinning this MSU-induced pyroptotic cascade in GA. Methods J774 cells were exposed to lipopolysaccharide and MSU crystals to establish in vitro GA models, whereas C57BL/6 J male mice received MSU crystal injections to mimic in vivo GA conditions. Gene and protein expression levels were evaluated using real-time quantitative PCR, Western blotting, and immunohistochemical assays. Inflammatory markers were quantified via enzyme-linked immunosorbent assays. Pyroptosis was evaluated using immunofluorescence staining for caspase-1 and flow cytometry with caspase-1/propidium iodide staining. The interaction between MDM2 and PPARγ was analyzed through co-immunoprecipitation assays, whereas the interaction between BRD4 and the MDM2 promoter was examined using chromatin immunoprecipitation and dual-luciferase reporter assays. Mouse joint tissues were histopathologically evaluated using hematoxylin and eosin staining. Results In GA, PPARγ was downregulated, whereas its overexpression mitigated NLRP3 inflammasome activation and pyroptosis. MDM2, which was upregulated in GA, destabilized PPARγ through the ubiquitin–proteasome degradation pathway, whereas its silencing attenuated NLRP3 activation by elevating PPARγ levels. Concurrently, BRD4 was elevated in GA and exacerbated NLRP3 activation and pyroptosis by transcriptionally upregulating MDM2, thereby promoting PPARγ degradation. In vivo experiments showed that BRD4 silencing ameliorated GA through this MDM2–PPARγ–pyroptosis axis. Conclusion BRD4 promotes inflammation and pyroptosis in GA through MDM2-mediated PPARγ degradation, underscoring the therapeutic potential of targeting this pathway in GA management.

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“…It was shown that EGFR activation can induce ubiquitination and degradation of PPARg (Xu et al, 2016). Although several reports show that PPARg agonists regulate EGFR signaling, almost all of these studies suggest that these effects on EGFR signaling are independent of PPARg activation (Mansure et al, 2013;Shi et al, 2016). The relationship between EGFR inhibition and PPARg activation regulated by HD-SB needs further investigation.…”

Section: Discussionmentioning

confidence: 95%

“…The result showed that p-EGFR and HSP90 were significantly down-regulated, whereas PPARg was significantly up-regulated after HD-SB treatment, compared with HD or SB treatment. Because p-EGFR and PPARg are related with cell apoptosis (Shi et al, 2016;Jackson and Ceresa, 2017), apoptosis rates and apoptosis-related proteins were also determined in cells treated with HD, SB, and HD-SB. It was found that HD-SB treatment significantly decreased bcl-2 expression; increased bax, cleaved caspase 3, cleaved PARP, p-AKT, and p-PI3K; and finally induced cancer cell apoptosis (Figure 7).…”

Section: Discussionmentioning

confidence: 99%

Antitumor Effects and the Compatibility Mechanisms of Herb Pair Scleromitrion diffusum (Willd.) R. J. Wang–Sculellaria barbata D. Don

Zhan

Liu

et al. 2020

Front. Pharmacol.

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Herb pair Scleromitrion diffusum (Willd.) R. J. Wang (HD) and Scutellaria barbata D. Don (SB) has been most frequently used for cancer treatment in traditional Chinese medicine. This study aimed to explore the in vitro and in vivo antitumor effects of HD-SB extract and to elucidate the underlying compatibility mechanisms. HD, SB, and HD-SB extracts were prepared, and the components were detected by ultraperformance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry method. The in vitro antitumor effects of various concentrations of these extract were detected on several tumor cell lines using MTS assay. The in vivo antitumor effects were evaluated in Panc28 cells-bearing nude mice model. The compatibility mechanisms of herb pair HD-SB were evaluated based on the systems pharmacology strategy and then validated by cellular experiments. HD-SB extract was demonstrated to inhibit the proliferation of the cancer cell lines dose dependently by MTS assay. In vivo antitumor effects of HD-SB were much more potent than either of the two single herbs in Panc28 xenograft mice model. A total 29 active ingredients involved in antitumor effects were selected from HD and SB, and the "herb-composition-target-disease" network was constructed. Then, 58 cancerrelated targets and 66 KEGG pathways were identified, and PTGS2-, HSP90-, EGFR-, MMP2-, PPARg-, and GSTP-mediated pathways were predicted to be the antitumor mechanisms of HD-SB. The cellular experiments showed that HD-SB significantly induced cancer cell apoptosis, decreased p-EGFR, HSP90 and bcl-2 expressions, and increased PPARg, bax, cleaved caspase 3, cleaved PARP, p-AKT, and p-PI3K expressions compared with HD or SB treatment. Our study showed that HD-SB inhibited tumor growth both in vitro and in vivo, which might be related with apoptosis induction via the EGFR/PPARg/PI3K/AKT pathway.

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Pioglitazone inhibits EGFR/MDM2 signaling-mediated PPARγ degradation

Cited by 12 publications

References 30 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

BRD4 promotes gouty arthritis through MDM2-mediated PPARγ degradation and pyroptosis

Antitumor Effects and the Compatibility Mechanisms of Herb Pair Scleromitrion diffusum (Willd.) R. J. Wang–Sculellaria barbata D. Don

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