title: FBXW7 influences murine intestinal homeostasis and cancer, targeting Notch, Jun, and DEK for degradation.
abstract: The Fbxw7 (F-box/WD repeat-containing protein 7; also called CDC4, Sel10, Ago, and Fbw7) component of the SCF (Skp1/Cullin/F-box protein) E3 ubiquitin ligase complex acts as a tumor suppressor in several tissues and targets multiple transcriptional activators and protooncogenes for ubiquitin-mediated degradation. To understand Fbxw7 function in the murine intestine, in this study, we specifically deleted Fbxw7 in the murine gut using Villin-Cre (Fbxw7(ΔG)). In wild-type mice, loss of Fbxw7 in the gut altered homeostasis of the intestinal epithelium, resulted in elevated Notch and c-Jun expression, and induced development of adenomas at 9-10 mo of age. In the context of APC (adenomatous polyposis coli) deficiency (Apc(Min/+) mice), loss of Fbxw7 accelerated intestinal tumorigenesis and death and promoted accumulation of β-catenin in adenomas at late but not early time points. At early time points, Fbxw7 mutant tumors showed accumulation of the DEK protooncogene. DEK expression promoted cell division and altered splicing of tropomyosin (TPM) RNA, which may also influence cell proliferation. DEK accumulation and altered TPM RNA splicing were also detected in FBXW7 mutant human colorectal tumor tissues. Given their reduced lifespan and increased incidence of intestinal tumors, Apc(Min/+)Fbxw7(ΔG) mice may be used for testing carcinogenicity and drug screening.
authors.affiliation: Division of Pre-Clinical Oncology, School of Clinical Sciences, University of Nottingham, Nottingham, England, UK.
authors.forename: Roya
authors.initials: R
authors.lastname: Babaei-Jadidi
authors.forename: Ningning
authors.initials: N
authors.lastname: Li
authors.forename: Anas
authors.initials: A
authors.lastname: Saadeddin
authors.forename: Bradley
authors.initials: B
authors.lastname: Spencer-Dene
authors.forename: Anett
authors.initials: A
authors.lastname: Jandke
authors.forename: Belal
authors.initials: B
authors.lastname: Muhammad
authors.forename: ElSayed E
authors.initials: EE
authors.lastname: Ibrahim
authors.forename: Ranjithmenon
authors.initials: R
authors.lastname: Muraleedharan
authors.forename: Mohammed
authors.initials: M
authors.lastname: Abuzinadah
authors.forename: Hayley
authors.initials: H
authors.lastname: Davis
authors.forename: Annabelle
authors.initials: A
authors.lastname: Lewis
authors.forename: Susan
authors.initials: S
authors.lastname: Watson
authors.forename: Axel
authors.initials: A
authors.lastname: Behrens
authors.forename: Ian
authors.initials: I
authors.lastname: Tomlinson
authors.forename: Abdolrahman Shams
authors.initials: AS
authors.lastname: Nateri
mesh_terms: D000236:Adenoma / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D003114:Colony-Forming Units Assay; D004268:DNA-Binding Proteins / Q000378:metabolism; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D000073979:F-Box-WD Repeat-Containing Protein 7; D017353:Gene Deletion; D006652:Histological Techniques; D006706:Homeostasis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D006801:Humans; D017403:In Situ Hybridization; D007413:Intestinal Mucosa / Q000378:metabolism; D007414:Intestinal Neoplasms / Q000378:metabolism*; D007422:Intestines / Q000502:physiology*; D051379:Mice; D016759:Oncogene Protein p65(gag-jun) / Q000378:metabolism; D015513:Oncogene Proteins / Q000378:metabolism; D000075223:Poly-ADP-Ribose Binding Proteins; D051880:Receptors, Notch / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis; D025521:Tumor Suppressor Proteins / Q000378:metabolism / Q000494:pharmacology*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*
chemical_list: C519564:DEK protein, mouse; D004268:DNA-Binding Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513272:Fbxw7 protein, mouse; D016759:Oncogene Protein p65(gag-jun); D015513:Oncogene Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D051880:Receptors, Notch; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases