The Novel Ubiquitin Ligase Complex, SCFFbxw4, Interacts with the COP9 Signalosome in an F-Box Dependent Manner, Is Mutated, Lost and Under-Expressed in Human Cancers Journal Article
| Authors: | Lockwood, W. W.; Chandel, S. K.; Stewart, G. L.; Erdjument-Bromage, H.; Beverly, L. J. |
| Article Title: | The Novel Ubiquitin Ligase Complex, SCFFbxw4, Interacts with the COP9 Signalosome in an F-Box Dependent Manner, Is Mutated, Lost and Under-Expressed in Human Cancers |
| Abstract: | Identification of novel proteins that can potentially contribute to carcinogenesis is a requisite venture. Herein, we report the first biochemical characterization of the novel F-box and WD40 containing protein, FBXW4. We have identified interacting protein partners and demonstrated that FBXW4 is part of a ubiquitin ligase complex. Furthermore, the Fbxw4 locus is a common site of proviral insertion in a variety of retroviral insertional mutagenesis murine cancer models and Fbxw4 mRNA is highly expressed in the involuting murine mammary gland. To begin to characterize the biochemical function of Fbxw4, we used proteomic analysis to demonstrate that Fbxw4 interacts with Skp1 (SKP1), Cullin1 (CUL1), Ring-box1 (RBX1) and all components of the COP9 signalosome. All of these interactions are dependent on an intact F-box domain of Fbxw4. Furthermore, Fbxw4 is capable of interacting with ubiquitinated proteins within cells in an F-box dependent manner. Finally, we demonstrate that FBXW4 is mutated, lost and under-expressed in a variety of human cancer cell lines and clinical patient samples. Importantly, expression of FBXW4 correlates with survival of patients with non-small cell lung cancer. Taken together, we suggest that FBXW4 may be a novel tumor suppressor that regulates important cellular processes. © 2013 Lockwood et al. |
| Keywords: | signal transduction; controlled study; protein expression; unclassified drug; oncoprotein; gene mutation; human cell; nonhuman; protein function; protein analysis; mouse; animal tissue; cell survival; ubiquitin protein ligase; protein protein interaction; lung non small cell cancer; gene locus; immunoreactivity; proteomics; gene expression regulation; tumor suppressor gene; ubiquitination; murinae; malignant neoplastic disease; antibody specificity; mutagenesis; mammary gland; transposon; cullin; genetic database; neddylation; f box protein; s phase kinase associated protein; cop9 signalosome; chemoluminescence; protein scf fbxw4; fbxw4 gene |
| Journal Title: | PLoS ONE |
| Volume: | 8 |
| Issue: | 5 |
| ISSN: | 1932-6203 |
| Publisher: | Public Library of Science |
| Date Published: | 2013-05-02 |
| Start Page: | e63610 |
| Language: | English |
| DOI: | 10.1371/journal.pone.0063610 |
| PROVIDER: | scopus |
| PMCID: | PMC3642104 |
| PUBMED: | 23658844 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 3 June 2013" - "Source: Scopus" |
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