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  • Review Article
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Roles of F-box proteins in cancer

Nature Reviews Cancer volume 14, pages 233–247 (2014)Cite this article

Subjects

Key Points

  • F-box proteins have pivotal roles in the development and progression of human malignancies through governing the turnover of key factors that are involved in multiple cellular processes, including cell proliferation, apoptosis, invasion, angiogenesis and metastasis.

  • In order to determine the possible role for each of the 69 identified mammalian F-box proteins in tumorigenesis, we focused on summarizing experimental evidence derived from physiological mouse models, pathological gene alterations in cancer patients and biochemical substrates identified for respective F-box proteins.

  • F-box/WD repeat-containing protein 7 (FBXW7) exerts its tumour-suppressor role mostly by promoting the degradation of various oncoproteins that regulate important cellular processes including cell cycle progression, cellular metabolism, differentiation and apoptosis. Moreover, FBXW7 somatic mutations have been observed in various human cancers, and genetic ablation of Fbxw7 in different tissue settings predisposes mice to cancer.

  • S-phase kinase-associated protein 2 (SKP2) promotes tumorigenesis mostly by promoting the ubiquitylation and subsequent degradation of a cohort of tumour-suppressor proteins, including p27, p21, p130 and forkhead box protein O1 (FOXO1). Skp2 transgenic mouse models, and overexpression of SKP2 in various types of human cancers further support a role for SKP2 as a proto-oncoprotein.

  • β-transducin repeat-containing protein 1 (β-TRCP1) and β-TRCP2 exert their oncogenic or tumour-suppressive function in a tissue-specific, or cellular context-dependent manner.

  • For a subset of F-box proteins with emerging oncogenic or tumour-suppressive roles, genetic mouse models have been established to shed light on the potential role of these proteins in tumorigenesis. However, further additional compound or tissue-specific mouse models, as well as identification of downstream substrates, are necessary to clearly define the roles of these proteins in cancer.

  • F-box proteins with undetermined roles in tumorigenesis are defined for those members without studies from cancerous mouse models, although pathological genetic alterations or characterized tumour-associated substrates might have provided minimal support for their possible involvement in tumorigenesis.

  • Targeting F-box proteins, or F-box protein signalling pathways, could be an effective strategy for prevention or treatment of human cancers.>

Abstract

F-box proteins, which are the substrate-recognition subunits of SKP1–cullin 1–F-box protein (SCF) E3 ligase complexes, have pivotal roles in multiple cellular processes through ubiquitylation and subsequent degradation of target proteins. Dysregulation of F-box protein-mediated proteolysis leads to human malignancies. Notably, inhibitors that target F-box proteins have shown promising therapeutic potential, urging us to review the current understanding of how F-box proteins contribute to tumorigenesis. As the physiological functions for many of the 69 putative F-box proteins remain elusive, additional genetic and mechanistic studies will help to define the role of each F-box protein in tumorigenesis, thereby paving the road for the rational design of F-box protein-targeted anticancer therapies.

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Figure 1: Illustration of functional domains in the highlighted F-Box proteins, grouped by their potential functions in cancer that have been shown by available mouse models.
Figure 2: Different strategies for targeted therapy that aims to inhibit F-box E3 ligases on the basis of their roles in tumorigenesis.

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Acknowledgements

The authors sincerely apologize to all those colleagues whose important work was not cited in this paper owing to space limitations. They thank B. North, A. W. Lau, S. Shaik and other members of the Wei laboratory for critical reading and discussion of the manuscript. W.W. is an American Cancer Society (ACS) research scholar and a Leukemia & Lymphoma Society (LLS) research scholar. P.L. is supported by grant 5T32HL007893. H.I. is supported by grant AG041218. This work was supported by a grant from the National Natural Science Foundation of China (NSFC) (81172087) and the Priority Academic Program Development of Jiangsu Higher Education Institutions. This work was supported in part by US National Institutes of Health (NIH) grants to W.W. (GM089763, GM094777 and CA177910).

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  1. Zhiwei Wang and Pengda Liu: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, 02215, Massachusetts, USA

    Zhiwei Wang, Pengda Liu, Hiroyuki Inuzuka & Wenyi Wei

  2. The Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, the First Affiliated Hospital, Soochow University, 215123, Suzhou, P. R. China

    Zhiwei Wang

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Supplementary information

Supplementary information S1 (table)

Summary of identified ubiquitin substrates for the FBW7 tumor suppressor. (PDF 149 kb)

Supplementary information S2 (table)

Summary of identified ubiquitin substrates for the FBXW class of F-box proteins other than FBW7 and β-TRCP1/2. (PDF 113 kb)

Supplementary information S3 (table)

Summary of identified ubiquitin substrates for the FBXO class of F-box proteins. (PDF 182 kb)

Supplementary information S4 (table)

Summary of identified ubiquitin substrates for the Skp2 oncoprotein. (PDF 141 kb)

Supplementary information S5 (table)

Summary of identified ubiquitin substrates for β-TRCP1/2. (PDF 200 kb)

Supplementary information S6 (table)

Summary of identified ubiquitin substrates for the FBXL class of F-box proteins other than Skp2 (FBXL1). (PDF 140 kb)

PowerPoint slides

Glossary

Pancytopenia

A disease that is characterized by a reduction in the number of all formed elements in the blood, such as red cells, white cells and platelets.

ApcMin/+ mice

Mice with the multiple intestinal neoplasia (Min) mutation are predisposed to intestinal adenoma formation, which is a widely used mouse model for exploring the role of adenomatous polyposis coli (APC) in intestinal tumorigenesis.

Hamartomas

Benign tumour-like malformations composed of tissue elements that are normally found at a given site but that grow in a disorganized mass.

αβ-crystallin

A water-soluble structural protein that is found in the lens and the cornea of the eye, accounting for the transparency of the structure. It has also been identified in other tissues, such as the heart, and in aggressive breast tumours. Recent studies showed that it is a cofactor for SKP1–cullin 1–F-box protein (SCF)-F-box only 4 (FBXO4)-mediated ubiquitylation of cyclin D1.

Mouse mammary tumour virus promoter

(MMTV promoter). The MMTV promoter is hormonally regulated and its expression is found primarily in the mammary gland and other tissues, such as the lung, kidney, salivary gland, testes and the prostate. The MMTV promoter is often used in model systems of breast cancer to elucidate the genetics and biology of breast cancer.

DMBA–TPA model

A two-stage chemical skin carcinogenesis model using a single dose of the genotoxic carcinogen DMBA, followed by multiple doses of a non-genotoxic tumour-promoter, TPA.

Split hand/foot malformation disease

(SHFM disease). A congenital limb defect that predominantly affects the central rays of the autopod.

Cancer testis antigen

A member of a group of tumour antigens with higher expression in normal testis but not in adult somatic tissues. Overexpression of cancer testis antigens has been observed in several types of human cancers, suggesting that they could be used as biomarkers and are attractive drug targets for cancer treatment.

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Wang, Z., Liu, P., Inuzuka, H. et al. Roles of F-box proteins in cancer. Nat Rev Cancer 14, 233–247 (2014). https://doi.org/10.1038/nrc3700

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