Flightless-1, a novel transcriptional modulator of PPARγ through competing with RXRα

Choi, Jin Woo; Choi, Sooyoung; Kim, Eun Sun; Seo, Young‐Kyo; Seo, Jeong Kon; Kim, Eung-Kyun; Suh, Pann‐Ghill; Choi, Jang Hyun

doi:10.1016/j.cellsig.2014.11.035

Cited by 16 publications

(15 citation statements)

References 32 publications

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“…The PVDF membrane was then blocked with 5% skim milk in PBS for 1 hour and incubated for 16 hour with 0.1 μmol/L GST-fused A/B domain, the DNA binding domain (DBD) including hinge region, the ligand binding domain (LBD), and full-length (FL) PPARγ proteins 27 in assay buffer (20 mmol/L potassium phosphate (pH 8.0), 50 mmol/L potassium chloride) at 4°C. The PVDF membrane was then blocked with 5% skim milk in PBS for 1 hour and incubated for 16 hour with 0.1 μmol/L GST-fused A/B domain, the DNA binding domain (DBD) including hinge region, the ligand binding domain (LBD), and full-length (FL) PPARγ proteins 27 in assay buffer (20 mmol/L potassium phosphate (pH 8.0), 50 mmol/L potassium chloride) at 4°C.…”

Section: Protein-lipid Overlay Assaymentioning

confidence: 99%

Glucosylceramide synthase regulates adipo‐osteogenic differentiation through synergistic activation of PPARγ with GlcCer

et al. 2019

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Abbreviations: A/B, N-terminal regulatory domain; AIM, adipogenic induction medium; ALP, alkaline phosphatase; AMP-DNM, N-(5-adamantane-1-ylmethoxy-pentyl)-deoxynojirimycin; aP2, adipocyte protein 2; ATF2, activating transcription factor 2; BMP2, bone morphogenetic protein 2; BV, bone volume; C/EBPα, CCAAT-enhancer binding protein α AbstractDysregulation of the adipo-osteogenic differentiation balance of mesenchymal stem cells (MSCs), which are common progenitor cells of adipocytes and osteoblasts, has been associated with many pathophysiologic diseases, such as obesity, osteopenia, and osteoporosis. Growing evidence suggests that lipid metabolism is crucial for maintaining stem cell homeostasis and cell differentiation; however, the detailed underlying mechanisms are largely unknown. Here, we demonstrate that glucosylceramide (GlcCer) and its synthase, glucosylceramide synthase (GCS), are key determinants of MSC differentiation into adipocytes or osteoblasts. GCS expression was increased during adipogenesis and decreased during osteogenesis. Targeting GCS using RNA interference or a chemical inhibitor enhanced osteogenesis and inhibited adipogenesis by controlling the transcriptional activity of peroxisome proliferator-activated receptor γ (PPARγ). Treatment with GlcCer sufficiently rescued adipogenesis and inhibited osteogenesis in GCS knockdown MSCs. Mechanistically, GlcCer interacted directly with PPARγ through A/B domain and synergistically enhanced rosiglitazone-induced PPARγ activation without changing PPARγ expression, thereby treatment with exogenous GlcCer increased adipogenesis and inhibited osteogenesis. Animal studies demonstrated that inhibiting GCS reduced adipocyte formation in white adipose tissues under normal chow diet and high-fat diet feeding and accelerated bone repair in a calvarial defect model. Taken together, our findings identify a novel lipid metabolic regulator for the control of MSC differentiation and may have important therapeutic implications.

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Section: Protein-lipid Overlay Assaymentioning

confidence: 99%

Glucosylceramide synthase regulates adipo‐osteogenic differentiation through synergistic activation of PPARγ with GlcCer

et al. 2019

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“…Flightless I (Flii) is a multifunctional member of the gelsolin family of actin‐remodelling proteins and a nuclear receptor coactivator affecting the transcriptional activity of modulators that affect tissue remodelling and inflammation . Both extracellular and intracellular forms of Flii modulate tissue inflammation via its interactions with TLRs.…”

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confidence: 99%

Reducing Flightless I expression decreases severity of psoriasis in an imiquimod-induced murine model of psoriasiform dermatitis

et al. 2016

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“…14, 16, 17) and suppressed PPARg, b-catenin, and ChREBP-mediated transcription in cancer cells (15,18,19). Currently, it was unknown whether FLII played a role in AR function.…”

Section: Resultsmentioning

confidence: 99%

“…FLII can be recruited by hormone-activated nuclear receptors to the promoters of target genes to serve as a coactivator of the nuclear receptor transcription complex (14,16,17). FLII also negatively regulates PPARg, b-catenin, and ChREBP-mediated transcription in cancer cells (15,18,19). It is currently unknown whether FLII plays a role in AR function during prostate cancer development.…”

Section: Introductionmentioning

confidence: 99%

Flightless I Homolog Represses Prostate Cancer Progression through Targeting Androgen Receptor Signaling

Wang

Song

Chen

et al. 2016

Clinical Cancer Research

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Purpose: Flightless I (FLII), member of the gelsolin superfamily of actin-remodeling proteins, functions as a transcriptional coregulator. We aim to evaluate a tumor-suppressive function of FLII in regulating androgen receptor (AR) in prostate cancer progression.Experimental Design: We examined FLII protein and mRNA expression in clinical prostate cancer specimens by immunohistochemistry. Kaplan-Meier analysis was conducted to evaluate the difference in disease-overall survival associated with the expression levels of FLII and AR. Prostate cancer cells stably expressing FLII or shRNA knockdown were used for functional analyses. Immunoprecipitation, Luciferase reporter, and immunofluorescence staining assays were performed to examine the functional interaction between FLII and AR.Results: Our analysis of the expression levels of FLII in a clinical gene expression array dataset showed that the expression of FLII was positively correlated with the overall survival of prostate cancer patients exhibiting high levels of AR expression. Examination of protein and mRNA levels of FLII showed a significant decrease of FLII expression in human prostate cancers. AR and FLII formed a complex in a ligand-dependent manner through the ligand-binding domain (LBD) of AR. Subsequently, we observed a competitive binding to AR between FLII and the ligand. FLII inhibited AR transactivation and decreased AR nuclear localization. Furthermore, FLII contributed to castration-sensitive and castration-resistant prostate cancer cell growth through AR-dependent signaling, and reintroduction of FLII in prostate cancer cells sensitized the cells to bicalutamide and enzalutamide treatment.Conclusions: FLII plays a tumor-suppressive role and serves as a crucial determinant of resistance of prostate cancer to endocrine therapies.

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Flightless-1, a novel transcriptional modulator of PPARγ through competing with RXRα

Cited by 16 publications

References 32 publications

Glucosylceramide synthase regulates adipo‐osteogenic differentiation through synergistic activation of PPARγ with GlcCer

Glucosylceramide synthase regulates adipo‐osteogenic differentiation through synergistic activation of PPARγ with GlcCer

Reducing Flightless I expression decreases severity of psoriasis in an imiquimod-induced murine model of psoriasiform dermatitis

Flightless I Homolog Represses Prostate Cancer Progression through Targeting Androgen Receptor Signaling

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