FBXW7 influences murine intestinal homeostasis and cancer, targeting Notch, Jun, and DEK for degradation

Area of Science:

• Molecular Biology
• Oncology
• Genetics

Background:

• The SCF (Skp1/Cullin/F-box protein) E3 ubiquitin ligase complex, specifically the Fbxw7 (F-box/WD repeat-containing protein 7) component, functions as a tumor suppressor.
• Fbxw7 targets key transcriptional activators and protooncogenes for degradation, regulating cellular processes.

Purpose of the Study:

• To investigate the role of Fbxw7 in the murine intestine by creating a specific knockout model (Fbxw7(ΔG)) using Villin-Cre.
• To elucidate the impact of Fbxw7 loss on intestinal homeostasis, signaling pathways, and tumor development, both in isolation and in combination with Apc deficiency.

Main Methods:

• Generation of a conditional knockout mouse model with Fbxw7 specifically deleted in the gut (Fbxw7(ΔG)).
• Analysis of intestinal epithelium homeostasis, gene expression (Notch, c-Jun, β-catenin, DEK), and tumor development in wild-type and Apc(Min/+) mice with Fbxw7 deficiency.
• Assessment of RNA splicing alterations, specifically tropomyosin (TPM), in Fbxw7 mutant tumors.

Main Results:

• Loss of Fbxw7 in the murine gut disrupted homeostasis, elevated Notch and c-Jun, and led to adenoma formation.
• In Apc(Min/+) mice, Fbxw7 deficiency accelerated intestinal tumorigenesis, shortened lifespan, and promoted β-catenin accumulation at later stages.
• Early-stage Fbxw7 mutant tumors showed DEK protooncogene accumulation, which influenced cell division and TPM RNA splicing, findings also observed in human colorectal tumors.

Conclusions:

• Fbxw7 is crucial for maintaining intestinal homeostasis and suppressing tumor development.
• The Apc(Min/+)Fbxw7(ΔG) mouse model is a valuable tool for carcinogenicity testing and drug screening due to its accelerated tumor development and reduced lifespan.