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Ret finger protein deficiency attenuates adipogenesis in high fat diet-induced obese mice

ABSTRACT: Ret finger protein (RFP, also known as TRIM27) is a multifunctional protein involved in tumor suppression and transcriptional regulation. While our previous studies revealed RFP's inhibitory role in myogenesis through MyoD regulation, its function in lipid metabolism remained unknown. Here, we investigated the effects of RFP deficiency on adipose metabolism in high-fat diet (HFD)-induced obesity. RFP knockout mice showed significantly reduced weight gain and fat accumulation, along with improved glucose levels and insulin sensitivity compared to wild-type controls. These metabolic improvements were replicated in adipocyte-specific RFP knockout mice. In vitro studies using 3T3-L1 adipocytes demonstrated that RFP regulates adipogenic gene expression through interaction with PPAR-γ and interference with its transcriptional activity. Our findings identify RFP as a key regulator balancing skeletal muscle and adipocyte maturation, suggesting that RFP inhibition could be a potential therapeutic target for obesity and metabolic disorders.

ORGANISM(S): Mus musculus

PROVIDER: GSE283657 | GEO | 2025/12/02

REPOSITORIES: GEO

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Project description:RET fusions (e.g., with KIF5B, CCDC6, and NCOA4) drive subsets of non-small cell lung cancer (NSCLC) and papillary thyroid carcinoma (PTC). Despite improvements in precision therapy using selective RET tyrosine kinase inhibitors (TKIs), resistance occurs and is often driven by RET-independent bypass mechanisms. SRC is a non-receptor tyrosine kinase and a well-known oncogene promoting proliferation, migration, stemness, etc. Although previous studies have implied crosstalk between RET and SRC, the anti-cancer effects of targeting SRC combined with first line RETi treatment, and their related molecular mechanisms are still not fully elucidated. Thus, we aimed to determine whether SRC inhibition enhances the anti-cancer effects of RET TKIs to create a combination strategy to treat RET fusion-positive (RET+) NSCLC and PTC. Our results showed that the SRC TKI, dasatinib, significantly enhanced the anti-cancer activities of RET TKIs in vitro. From phosphoproteomics analysis and validation assays using selective inhibitors and siRNAs, we have defined that dasatinib synergizes with RET TKIs through further suppression of PAK, AKT and S6 signaling pathways. Moreover, rescue experiments using SRC gatekeeper mutation (T341I) further validated that the combination effects between RET TKIs and dasatinib were SRC-dependent. Importantly, we also observed synergistic effects in RET+ cancer cells between RET TKIs and eCF506, a next-generation clinical SRC inhibitor with higher selectivity. Finally, both dasatinib and scF506 could restore selpercatinib sensitivity in a selpercatinib-resistant RET+ PTC cell line. Altogether, our results suggest that SRC and RET signaling crosstalk to activate RET canonical and non-canonical downstream pathways in RET+ NSCLC and PTC and that SRC inhibition has clinical potential against TKI-naïve and -resistant RET+ cancers.The experimental design for the tandem mass tag labeling was: DMSO (126, 127CC, 128C), DMSO 24 hrs. (127N, 128N, 129N), Pralsetinib 3 hrs. (129C, 130C, 131C), Pralsetinib 24 hrs. (130N, 131N, 132N), Dasatinib 3 hrs. (132C, 133C, 134C), PralDasa Combination 3 hrs. (133N, 134N, 135N). In the filenames, ID indicates expression proteomics; IMAC indicates phosphoproteomics.

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Ret finger protein deficiency attenuates adipogenesis in high fat diet-induced obese mice

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