C49
Fbxw7 (hCDC4) E3-ubiquitin ligase receptor: lineage potential and its commitment to cancer
NingNing Li1, Ranjith Muraleedharan1, Ke Wang1, Amir Ghaemmaghami1, Anas Saadeddin1, Bradley Spencer-Dene2, Sue Watson1, Abdolrahman Shams Nateri1
1University of Nottingham, UK, 2London Research Institute, Cancer Research UK, Nottingham, UK
Cell cycle control at the sub-cellular level determines the development of eukaryotic organisms on a macro scale; it is, however, decisively dependent on the ubiquitin-mediated degradation of major cell-cycle regulatory proteins. Fbxw7 (F-box and WD repeat domain) constitutes the F-box protein subunit, known as the substrate recognition component of an SCF-type ubiquitin ligase complex, which is crucial liaison of the ubiquitin proteolytic system (UPS). Canonically, as a tumour suppressor Fbxw7 promotes cell cycle exit by targeting its substrates, including number of growth activators; c-Myc, c-Jun, Cyclin E, Notch1, Notch4, to UPS.
The Adenomatous Polyposis Coli (Apc) is a known tumour suppressor gene and is found mutated in most familial and sporadic colorectal cancers. APC protein, an effector of Wnt pathway, binds directly to microtubules. Lack of APC results in defective mitotic spindles and aneuploidy owing to mis-segregation of chromosomes. Increasing reports indicate that loss-of-function Fbw7 may trigger cancer via genomic instability. To this end, Fbxw7 and APC may orchestrate gatekeeping of the genome.
APC also binds to and sequester cytosolic beta-catenin, which are cardinal effectors of Wnt pathway and a transactivator of some Fbxw7 substrates. The mechanism underlying the converging roles of Fbxw7 and Wnt remained largely unknown. To elucidate; 1) how Fbxw7 coordinates with APS, as well as with other oncosuppressor proteins, to keep cells under rigorous surveillance off cancers, and 2). the commitments of Fbxw7 and APC to stem cell maintenance, we perform mass spectrometry-based proteolytic mapping for a wider Fbxw7/APCmediated network by comparing intestinal crypt samples from four mouse models: Fbxw7f/f, Fbxw7ΔG, APCMin, and F7Mduo. Conditional knockout mice Fbxw7ΔG lack functional Fbw7 in the whole intestine. An APCMin mouse with germline inactivation of one Apc allele mimics the rapid development of adenomatous polyps in humans. The double mutant mice F7Mduo are from crossbreeding of Fbxw7ΔG and APCmin. Our preliminary data show that some of the novel Fbxw7- interacting partners may be related to genomic instability. More intriguingly, our F7Mduo mice develop multiple neoplasms with a distribution throughout the colon and small intestine in comparison with small scale of tumorigenicity only in colon from Fbxw7ΔG and APCMin. Take together, our findings may provide new insights into coordination and contribution of Fbxw7 and APC toward oncosuppression and anti-metastasis.
