PPARγ is a tumor suppressor in basal bladder tumors offering new potential therapeutic opportunities

L, Coutos-Thévenot; Beji, Sara; Neyret‐Kahn, Hélène; Pippo, Q; Fontugne, Jacqueline; Ősz, Judit; Krucker, Clémentine; Cds, Groeneveld; Dufour, Florent; Kamoun, Aurélie; M, Ley; Chapeaublanc, Élodie; Ad, Reynies; Lebrét, Thierry; Allory, Yves; Cianférani, Sarah; Radvanyi, François; Rochel, Natacha; Bernard‐Pierrot, Isabelle

doi:10.1101/868190

Cited by 3 publications

(3 citation statements)

References 48 publications

(78 reference statements)

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“…In basal bladder tumors, four non-recurrent loss-of-function PPARg mutations (S74C, F310S, E455Q, and H494Y, Figure 2) have been identified (130). All four PPARg mutants display significantly reduced transcriptional activities.…”

Section: Loss-of-function Mutationsmentioning

confidence: 99%

“…Biochemical and biophysical analysis of amino acid residues F310 and H494, situated in helix 3 and 12, respectively, indicated that both residues are essential for proper stabilization of helix 12. F310S and H494Y favor an inactive conformation, impairing both a proper release of corepressors and recruitment of coactivators (130). Basal tumors rely on EGFR signaling for growth (131).…”

Section: Loss-of-function Mutationsmentioning

confidence: 99%

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PPARgamma in Metabolism, Immunity, and Cancer: Unified and Diverse Mechanisms of Action

2021

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The proliferator-activated receptor γ (PPARγ), a member of the nuclear receptor superfamily, is one of the most extensively studied ligand-inducible transcription factors. Since its identification in the early 1990s, PPARγ is best known for its critical role in adipocyte differentiation, maintenance, and function. Emerging evidence indicates that PPARγ is also important for the maturation and function of various immune system-related cell types, such as monocytes/macrophages, dendritic cells, and lymphocytes. Furthermore, PPARγ controls cell proliferation in various other tissues and organs, including colon, breast, prostate, and bladder, and dysregulation of PPARγ signaling is linked to tumor development in these organs. Recent studies have shed new light on PPARγ (dys)function in these three biological settings, showing unified and diverse mechanisms of action. Classical transactivation—where PPARγ activates genes upon binding to PPAR response elements as a heterodimer with RXRα—is important in all three settings, as underscored by natural loss-of-function mutations in FPLD3 and loss- and gain-of-function mutations in tumors. Transrepression—where PPARγ alters gene expression independent of DNA binding—is particularly relevant in immune cells. Interestingly, gene translocations resulting in fusion of PPARγ with other gene products, which are unique to specific carcinomas, present a third mode of action, as they potentially alter PPARγ’s target gene profile. Improved understanding of the molecular mechanism underlying PPARγ activity in the complex regulatory networks in metabolism, cancer, and inflammation may help to define novel potential therapeutic strategies for prevention and treatment of obesity, diabetes, or cancer.

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Section: Loss-of-function Mutationsmentioning

confidence: 99%

Section: Loss-of-function Mutationsmentioning

confidence: 99%

PPARgamma in Metabolism, Immunity, and Cancer: Unified and Diverse Mechanisms of Action

2021

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“…A previous study showed that PPARγ F310S mutation was associated with basal bladder tumors. Further biochemical and structure-function analysis showed that the F310S mutation decreases PPARγ activity through the destabilization of helix 12, thereby impairing the release of corepressors and the recruitment of coactivators ( 16 ). Moreover, mechanisms of negative dominance and haploinsufficiency have both been suggested to explain the pathogenicity of PPARG mutations.…”

Section: Discussionmentioning

confidence: 99%

Case Report: A New Peroxisome Proliferator-Activated Receptor Gamma Mutation Causes Familial Partial Lipodystrophy Type 3 in a Chinese Patient

Chen

et al. 2022

Front. Endocrinol.

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PurposeFamilial partial lipodystrophy type 3 (FPLD3) is an autosomal dominant disease. Patients typically present with loss of adipose tissue and metabolic complications. Here, we reported a Chinese FPLD3 patient with a novel PPARG gene mutation.MethodsA 16-year-old female patient and her relatives were assessed by detailed clinical and biochemical examinations. Sequencing was performed by using the extracted DNA. Moreover, we identified FPLD3 patients from previous studies, and according to the protein region affected by the gene mutation. We divided the patients into the DNA-binding domain (DBD) group or the ligand-binding domain (LBD) group, and compared the clinical features between the two groups.ResultsWe identified a novel gene mutation affecting the LBD of PPARγ c.929T > C (p.F310S). This mutation leads to the substitution of a phenylalanine by a serine. In our case, subcutaneous fat was significantly diminished in her face, hips and limbs. The patient was also presented with insulin resistance, diabetes mellitus, hypertriglyceridemia, fatty liver, liver dysfunction, albuminuria and diabetic peripheral neuropathy. After literature review, a total of 58 FPLD3 patients were identified and we found no difference in clinical features between the DBD group and LBD group (all P > 0.05).ConclusionsA Chinese FPLD3 patient with a novel PPARG gene mutation is described. Our case emphasized the importance of physical examination and genetic testing in young patients with severe metabolic syndromes.

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The urothelial gene regulatory network: understanding biology to improve bladder cancer management

Ramal,

Corral,

Kalisz

et al. 2023

Oncogene

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PPARγ is a tumor suppressor in basal bladder tumors offering new potential therapeutic opportunities

Cited by 3 publications

References 48 publications

PPARgamma in Metabolism, Immunity, and Cancer: Unified and Diverse Mechanisms of Action

PPARgamma in Metabolism, Immunity, and Cancer: Unified and Diverse Mechanisms of Action

Case Report: A New Peroxisome Proliferator-Activated Receptor Gamma Mutation Causes Familial Partial Lipodystrophy Type 3 in a Chinese Patient

The urothelial gene regulatory network: understanding biology to improve bladder cancer management

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