Fbxw2-flox Mouse

Fbxw2, also known as F-box and WD-repeat-containing protein 2, is an E3 ubiquitin ligase, which is the substrate-binding subunit of E3 ubiquitin ligase SCF complex (composed of FBXW2, SKP1, and cullin-1). It plays a crucial role in regulating various biological processes through ubiquitination and degradation of its substrates, thus participating in multiple pathways related to tumorigenesis, inflammation, and cell stemness [1,2,3,4,5,6,7,8].

Myeloid-specific Fbxw2 gene deficiency in murine models improves obesity-associated insulin resistance and atherosclerosis, accompanied by decreased pro-inflammatory responses and macrophage infiltration. This indicates Fbxw2's role as an inflammatory mediator in macrophages [3]. In breast cancer, Fbxw2 overexpression suppresses breast cancer stemness, tumorigenesis, and paclitaxel resistance by ubiquitinating and degrading NF-κB p65. Also, it restricts the AKT-Moesin-SKP2 oncogenic axis to inhibit breast tumor growth [1,2]. In prostate cancer, overexpression of Fbxw2 attenuates proliferation and metastasis by promoting EGFR ubiquitylation and degradation [4]. In lung cancer, Fbxw2 inhibits migration, invasion, and metastasis by promoting β-catenin ubiquitylation and degradation, and also suppresses proliferation by targeting SKP2 for degradation [5,7]. In gastric cancer, Fbxw2 suppresses cancer progression by promoting β-catenin ubiquitination [8].

In conclusion, Fbxw2 functions as a tumor suppressor in multiple cancer types, including breast, prostate, lung, and gastric cancer, mainly through promoting the ubiquitination and degradation of key oncogenic proteins. In addition, it serves as an important mediator in metabolic diseases like obesity and atherosclerosis. Gene knockout models, especially in mice, have been crucial in revealing these functions, providing insights into potential therapeutic targets for related diseases.