FBXW7 in Cancer: What Has Been Unraveled Thus Far?

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Abstract

The FBXW7 (F-box with 7 tandem WD40) protein encoded by the gene FBXW7 is one of the crucial components of ubiquitin ligase called Skp1-Cullin1-F-box (SCF) complex that aids in the degradation of many oncoproteins via the ubiquitin-proteasome system (UPS) thus regulating cellular growth. FBXW7 is considered as a potent tumor suppressor as most of its target substrates can function as potential growth promoters, including c-Myc, Notch, cyclin E, c-JUN, and KLF5. Its regulators include p53, C/EBP-δ, Numb, microRNAs, Pin 1, Hes-5, BMI1, Ebp2. Mounting evidence has indicated the involvement of aberrant expression of FBXW7 for tumorigenesis. Moreover, numerous studies have also shown its role in cancer cell chemosensitization, thereby demonstrating the importance of FBXW7 in the development of curative cancer therapy. This comprehensive review emphasizes on the targets, functions, regulators and expression of FBXW7 in different cancers and its involvement in sensitizing cancer cells to chemotherapeutic drugs.

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Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal.

J. Gao, B. A. Aksoy, U Dogrusoz … (2015)

The cBioPortal for Cancer Genomics (http://cbioportal.org) provides a Web resource for exploring, visualizing, and analyzing multidimensional cancer genomics data. The portal reduces molecular profiling data from cancer tissues and cell lines into readily understandable genetic, epigenetic, gene expression, and proteomic events. The query interface combined with customized data storage enables researchers to interactively explore genetic alterations across samples, genes, and pathways and, when available in the underlying data, to link these to clinical outcomes. The portal provides graphical summaries of gene-level data from multiple platforms, network visualization and analysis, survival analysis, patient-centric queries, and software programmatic access. The intuitive Web interface of the portal makes complex cancer genomics profiles accessible to researchers and clinicians without requiring bioinformatics expertise, thus facilitating biological discoveries. Here, we provide a practical guide to the analysis and visualization features of the cBioPortal for Cancer Genomics.

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FBW7 ubiquitin ligase: a tumour suppressor at the crossroads of cell division, growth and differentiation.

Markus Welcker, Bruce Clurman (2008)

FBW7 (F-box and WD repeat domain-containing 7) is the substrate recognition component of an evolutionary conserved SCF (complex of SKP1, CUL1 and F-box protein)-type ubiquitin ligase. SCF(FBW7) degrades several proto-oncogenes that function in cellular growth and division pathways, including MYC, cyclin E, Notch and JUN. FBW7 is also a tumour suppressor, the regulatory network of which is perturbed in many human malignancies. Numerous cancer-associated mutations in FBW7 and its substrates have been identified, and loss of FBW7 function causes chromosomal instability and tumorigenesis. This Review focuses on structural and functional aspects of FBW7 and its role in the development of cancer.

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Structure of the Cul1-Rbx1-Skp1-F boxSkp2 SCF ubiquitin ligase complex.

Ning Zheng, Brenda Schulman, Langzhou Song … (2002)

SCF complexes are the largest family of E3 ubiquitin-protein ligases and mediate the ubiquitination of diverse regulatory and signalling proteins. Here we present the crystal structure of the Cul1-Rbx1-Skp1-F boxSkp2 SCF complex, which shows that Cul1 is an elongated protein that consists of a long stalk and a globular domain. The globular domain binds the RING finger protein Rbx1 through an intermolecular beta-sheet, forming a two-subunit catalytic core that recruits the ubiquitin-conjugating enzyme. The long stalk, which consists of three repeats of a novel five-helix motif, binds the Skp1-F boxSkp2 protein substrate-recognition complex at its tip. Cul1 serves as a rigid scaffold that organizes the Skp1-F boxSkp2 and Rbx1 subunits, holding them over 100 A apart. The structure suggests that Cul1 may contribute to catalysis through the positioning of the substrate and the ubiquitin-conjugating enzyme, and this model is supported by Cul1 mutations designed to eliminate the rigidity of the scaffold.

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Journal

Journal ID (nlm-ta): Cancers (Basel)

Journal ID (iso-abbrev): Cancers (Basel)

Journal ID (publisher-id): cancers

Title: Cancers

Publisher: MDPI

ISSN (Electronic): 2072-6694

Publication date (Electronic): 19 February 2019

Publication date Collection: February 2019

Volume: 11

Issue: 2

Electronic Location Identifier: 246

Affiliations

[1 ]Cancer Biology Laboratory and DBT-AIST International Laboratory for Advanced Biomedicine (DAILAB), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam 781039, India; bethsailo@ 123456gmail.com (B.L.S.); kishore.banik@ 123456iitg.ernet.in (K.B.); sosmi176106101@ 123456iitg.ac.in (S.G.); devivasha@ 123456iitg.ac.in (D.B.)

[2 ]Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117 600, Singapore; phcfanl@ 123456nus.edu.sg (L.F.); phsceh@ 123456nus.edu.sg (C.E.H.); snrwh@ 123456nus.edu.sg (H.W.); csiapk@ 123456nus.edu.sg (A.P.K.)

[3 ]Cancer Science Institute of Singapore, National University of Singapore, Singapore 117 600, Singapore

[4 ]Medical Science Cluster, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117 600, Singapore

[5 ]Curtin Medical School, Faculty of Health Sciences, Curtin University, Perth, WA 6845, Australia

[6 ]The School of Stomatology, Fujian Medical University, 1 Xue Yuan Road, University Town, Fuzhou 350108, Fujian, China; dalizheng@ 123456hotmail.com

[7 ]Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, 12 Jichang Road, Baiyun District, Guangzhou 510405, Guangdong, China; xinliangmao@ 123456suda.edu.cn

[8 ]Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, 199 Ren’ai Road, Suzhou 215123, Jiangsu, China

Author notes

[* ]Correspondence: phcgs@ 123456nus.edu.sg (G.S.); kunnumakkara@ 123456iitg.ac.in or ajai78@ 123456gmail.com (A.B.K.); Tel.: +91-361-258-2231 (Office) & +91-789-600-5326 (Mobile) (A.B.K.); +(65)-65163267 (G.S.); Fax: +91-361-258-2249 (Office) (A.B.K.); +(65)-68737690 (G.S.)

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Alan Prem Kumar https://orcid.org/0000-0002-3754-5712

Article

Publisher ID: cancers-11-00246

DOI: 10.3390/cancers11020246

PMC ID: 6406609

PubMed ID: 30791487

SO-VID: 713efb2a-4088-400a-a5fe-1d7947edf5ec

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Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

FBXW7 in Cancer: What Has Been Unraveled Thus Far?

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Abstract

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Cancer Metabolism

Most cited references 194

Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal.

FBW7 ubiquitin ligase: a tumour suppressor at the crossroads of cell division, growth and differentiation.

Structure of the Cul1-Rbx1-Skp1-F boxSkp2 SCF ubiquitin ligase complex.

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