Table 1.
RING finger E3s as oncogenes and tumour suppressor genes
| E3 | Function | Role in Cancer* | Refs |
|---|---|---|---|
| Cell Cycle | |||
| APC/C ligases | Multisubunit E3s that regulate the cell cycle. | Tumor suppressor complexes. Evidence of mutations in several subunits that disrupt function in colon cancer cells, resulting in increased accumulation of cyclins and progression of the cell cycle. Some experimental data suggest that compromised function of APC/C by loss of substrate recognition subunits, CDC20 or CDH1, can result in genomic instability consistent with a role for APC/C as a tumour suppressor | 7–9 |
| β–TrCP (FBW1A) | F-box protein, functions as a substrate recognition component of the SCF E3 complex, which is involved in degradation of phosphorylated cell cycle and signaling molecules. β–TrCP targets the SCF complex to multiple proteins that have both pro- and anti-proliferative effects such as BCL2L11 (also known as BimEL), CDC25A, β-catenin, IκB, PDCD4, SMAD3, SMAD4 and WEE1 | A potential oncogene. Transgenic mice overexpressing β–TrCP have an increased incidence of epithelial tumors. Consistent with its function as an oncogene, β–TrCP is overexpressed and associated with poor prognosis in many human epithelial cancers. However, β–TrCP mutations described in GI malignancies are associated with stabilization and the accumulation of nuclear β-catenin, consistent with a role as a TSG. This suggests that the oncogenic or tumour suppressive effects of β–TrCP are context-dependent | 5,13 |
| COP1 (RFWD2) | RING finger component of a multisubunit E3 that targets multiple transcription factors including members of the JUN and ETS family for proteasomal degradation. Also reported to target p53 for proteasomal degradation (see Supplementary information supplementary table 1) | A TSG. Rfwd2 hypomorphic mice develop thymic lymphomas, teratomas and uterine tumors. Rare deletions of RFWD2 have been described in lymphoblastic lymphoma, melanoma and prostate cancer. There is an inverse correlation between low COP1 expression and high expression of JUN and ETS family members in prostate cancer. Translocations of ETS family genes that delete COP1 binding sites stabilize ETS proteins | 158,159 |
| EMI1 (FBXO5) | Inhibits activity of APC/CCDH1 and allows progression from G1 to S phase. In some cells it also functions to inactivate APC/CCDC20 | A potential oncogene. EMI1 is overexpressed in breast, colon, ovarian, uterine and lung cancer. Predicted to allow cell cycle progression when APC/CCDH1 is inhibited | 160–162 |
| FBXW7 | F-box and WD repeat containing protein that functions as a recognition component of an SCF E3 complex. Substrates include cyclin E, MYC, NOTCH and JUN | A haploinsufficient TSG. Loss-of-function mutations identified in cholangiocarcinoma, T-ALL, breast, bladder, ovarian, liver, lung, bone and endometrial cancers. There is evidence that mutant alleles dimerize with and inhibit wild-type alleles | 10,163 |
| SKP2 | F-box protein that functions as a recognition component of the SCF E3 complex that targets p27 and other cell cycle proteins | An oncogene. SKP2 is amplified in human epithelial cancers including small cell and non-small-cell lung cancer, glioblastoma, squamous cell esophageal cancer, cervical cancer and thyroid cancer and overexpressed in many human tumors. Cooperates with activated RAS in transformation assays. Transgenic mice expressing SKP2 and activated NRAS develop lymphomas with increased frequency and decreased latency compared to activated NRAS alone. High expression of SKP2 correlates with high-grade lymphoma | 3,164–166 |
| Genomic integrity | |||
| BARD1 | RING finger protein without E3 activity. Heterodimerizes with BRCA1 and enhances BRCA1 E3 activity. Functions in HR DNA repair pathway | A TSG. Patients with familial breast cancer have been described with homozygous deletion or inactivating mutations | 56,167–169 |
| BRCA1 | RING finger E3. Functions in transcription and HR DNA repair pathway. | A TSG. Deleted or inactivated in patients with familial breast and ovarian cancer. | 56,170 |
| CUL7 | Cullin protein. Forms an SCF-like multisubunit E3 complex. Heterodimerizes with PARC (also known as CUL9) and inactivates p53 | A potential oncogene. Prevents MYC-induced apoptosis and cooperates with MYC in transformation assays. Appears to function by inactivating p53 | 171–173 |
| FANC core complex | Multisubunit E3 that monoubiquitylates FANCD2 and FANCI and regulates DNA repair. FANCL contains a RING finger-like PHD domain with E3 activity | A tumour suppressor. Mutations in individual FANC E3 subunits lead to Fanconi anaemia, which is associated with an increased risk of cancer | 73 |
| MDM2 | RING finger E3. Inactivates p53 by ubiquitylation and proteasomal degradation. Other substrates identified (see Supplementary information) | An oncogene. Transforming protein when overexpressed, it is amplified in human cancers.. | 15,174 |
| MDMX (MDM4) | RING finger protein without E3 activity. Dimerizes with MDM2 and enhances p53 ubiquitylation. | An oncogene. Enhances degradation of p53 by MDM2. Transforming protein when overexpressed. Amplified in human cancers. | 31,175–177 |
| PARC (CUL9) | Cullin-like protein that forms a multisubunit E3 complex with the RING finger protein RBX1. | A potential oncogene. Sequesters p53 in the cytoplasm and prevents p53 activation. | 172,178 |
| PIRH2 (RCHY) | RING finger E3 that ubiquitylates and targets p53 for proteasomal degradation | A potential oncogene. Overexpressed in lung cancer resulting in p53 degradation. For additional information see Supplementary Information (supplementary table 1). | 179,180 |
| Signal Transduction | |||
| CBLs | RING finger E3s that target activated kinases for ubiquitylation and degradation. | Oncogenes. Dominant-negative forms of Cbl act as oncogenes in mice and NIH-3T3 cells. Mutations that create dominant-negative forms of CBL have been found in human myeloid neoplasms. Mutations in CBL binding sites on kinases or in negative regulators of CBL have been described in various cancers. | 113 |
| FBXW5 | F-box and WD repeat protein. Substrate binding component of CRL4 E3 (CRL4FBW5) | A potential oncogene. Targets the tumour suppressor protein TSC2 for proteasomal degradation | 181 |
| Hakai (CBLL1) | Single subunit RING finger E3 that targets E-cadherin for degradation | A potential oncogene or prometastatic gene. Promotes cell migration, proliferation and anchorage-independent growth | 88,182 |
| IAPs | RING finger E3s that autoubiquitylate and ubiquitylate caspases and TRAFs. They regulate NF-κB signaling and also negatively regulate caspase activation | Oncogenes and/or TSGs that inhibit apoptosis and promote cell proliferation. Overexpressed in many malignancies. Translocations creating MALT1-cIAP2 fusion protein are seen in 25% of MALT lymphomas. These fusions delete the RING finger of cIAP2 and overexpression activates the NF-κB pathway. Homozygous deletions of the chromosome region containing BIRC2 and BIRC3 (which encode cIAP1 and cIAP2, respectively) described in multiple myeloma are associated with increased NF-κB activity | 95,183–187 |
| TRAFs | A family of RING finger E3s that positively and negatively regulate NF-κB activation | Oncogenes and/or TSGs. Missense mutations identified in TRAF2 and TRAF5 in 2–5% of B-cell lymphomas. Overexpression experiments of one such mutation in TRAF2 demonstrated increased NF-κB activity, although the mechanism is not defined. By contrast, inactivating mutations or homozygous deletions of TRAF2 and TRAF3 have been described in multiple myeloma associated with increased NF-κB activity and are consistent with a TSG function for these TRAFs | 183,186,188 |
| TRC8 (RNF139) | RING finger E3 with sterol sensing domain involved in protein biosynthesis | A TSG. Disruption of RNF139 by translocations is found in patients with familial clear cell renal cancer, patients with thyroid cancer, and a patient with dysgerminoma. Overexpression of TRC8 suppresses tumor cell growth | 189–191 |
| Hypoxia | |||
| VHL | Recognition component of the cullin based CRL2VHL E3 complex. Targets HIF transcription factors for degradation under conditions of normoxia | A TSG lost in von-Hippel Lindau syndrome, which is associated with CNS tumors, haemangioblastomas, pheochromocytomas and clear cell kidney cancer. VHL is inactivated in 40–80% of sporadic clear cell kidney cancer | 131–133 |
| SIAHs | RING finger E3s | Potential oncogenes. Ubiquitylates and targets proline hydroxylases for proteasomal degradation, which results in stabilization of HIFα transcription factors | 152,153 |
| Metastasis | |||
| gp78(AMFR) | RING finger E3 implicated in endoplasmic reticulum-associated degradation (ERAD). | A potential oncogene or prometastatic gene. Promotes sarcoma metastasis by degrading metastasis suppressor KAI1 (also known as CD82). | 192 |
β-TrCP, β-transducin repeat containing protein; AMFR, human tumor autocrine motility factor receptor; APC/C, anaphase-promoting complex/cyclosome; BARD1, BRCA1 associated RING domain 1; BIRC, baculoviral IAP repeat containing; CDC, cell division cycle; CNS, central nervous system; COP1, constitutive photomorphogenesis protein 1 homologue; CRL, cullin RING ligase; CUL, cullin; EMI1, early mitotic inhibitor 1; FANC, Fanconi anaemia; FBXW, F-box/WD-repeat containing protein; GI, gastrointestinal; HIF, hypoxia-inducible factor; HR, homologous recombination; KAI1, kangai 1; MALT, mucosa-associated lymphoid tissue lymphoma translocation; NF-κB, nuclear factor-κB; PDCD4, programmed cell death protein 4; PHD, plant homeodomain; RCHY, ring finger and CHY zinc finger domain containing 1; RFWD2, RING finger and WD repeat domain protein 2; RNF139, RING finger protein 139; SCF, SKP1-cullin 1-F-box protein; SIAH, seven in absentia homologue; SKP2, S-phase kinase-associated protein 2; T-ALL, T-cell acute lymphoblastic leukaemia; TRAF, TNF receptor-associated factor; TSC2, tuberin; TSG, tumour suppressor gene; VHL, von Hippel Lindau tumour suppressor.
*
Genes are designated as oncogenes or TSGs when there is functional evidence for their role in cancer and genetic mutations consistent with that role have been found in human cancers. For oncogenes this generally consists of activating mutations and/or gene amplification. For TSGs, this generally consists of inactivating mutations and/or deletions. Genes are designated as potential oncogenes or TSGs when functional studies are consistent with that role but no mutations have been reported in human tumors to date. In some instances a protein may act as an oncoprotein or a tumor suppressor depending on the cellular context.