RINGs of good and evil: RING finger ubiquitin ligases at the crossroads of tumour suppression and oncogenesis

Abstract

The ubiquitin-proteasome system has numerous crucial roles in physiology and pathophysiology. Fundamental to the specificity of this system are ubiquitin-protein ligases (E3s). Of these, the majority are RING finger and RING finger-related E3s. Many RING finger E3s have roles in processes that are central to the maintenance of genomic integrity and cellular homeostasis, such as the anaphase promoting complex/cyclosome (APC/C), the SKP1-cullin 1-F-box protein (SCF) E3s, MDM2, BRCA1, Fanconi anaemia proteins, CBL proteins, von Hippel-Lindau tumour suppressor (VHL) and SIAH proteins. As a result, many RING finger E3s are implicated in either the suppression or the progression of cancer. This Review summarizes current knowledge in this area.

Figure 1. MDM2

a | A linear representation of MDM2 showing defined domains (boundaries are approximate). MDMX (also known as MDM4) has a similar domain structure but lacks the nuclear localization signal (NLS), the nucleolar localization signal (NoLS), and the nuclear export signal (NES) found in MDM2. Interacting proteins are listed below the domains of MDM2 with which they interact, site of Nutlin binding is also shown. b | MDM2, predominantly as a dimer with MDMX (not shown), binds in vivo to and ubiquitylates p53, which exists largely as a tetramer. This results in the proteasomal degradation of p53. c | In response to genotoxic and other stresses, kinases and acetylases promote the modification of p53 as well as MDM2 such that their binding is reduced and sites of ubiquitylation are unavailable. Additionally, expression of ARF is increased and small ribosome subunits become available. These inhibit the activity of MDM2 towards p53 and result in targeting MDM2 to the nucleolus and potentially increase autoubiquitylation and degradation of MDM2 in the context of the homodimer. This degradation may be further facilitated by stress-induced phosphorylation of MDM2 leading to decreased binding of herpes virus-associated ubiquitin-specific protease (HAUSP; also known as USP7; not shown). As a consequence of its stabilization and dissociation from MDM2 p53 activity increases, resulting in the induction of growth arrest proteins (such as p21) or pro-apoptotic proteins (such as the BH3 only proteins p53-upregulated modulator of apoptosis (PUMA) and NOXA) as well as increased MDM2 expression. Figure reproduced with permission © Macmillan Publishers (2011).

Figure 2. CBL

a | Schematic structure of the vCBL and CBL proteins. The tyrosine kinase-binding (TKB) domain is comprised of a 4-helix bundle (4H), an EF hand (EF), and a variant SH2 domain (SH2). The linker (L), RING finger (RF), proline-rich (P), and the ubiquitin-associated (UBA) domains are indicated. The tyrosines (Y) at sites of phosphorylation in the C-terminal of CBL are also indicated. b | CBL proteins mediate ubiquitylation and downregulation of receptor tyrosine kinases (RTKs). Whether CBL proteins associated with activated complexes are degraded in lysosomes or proteasomes is unresolved. Figure reproduced with permission © Macmillan Publishers (2011).

Figure 3. Hypoxia

Hypoxia-inducible factor-α (HIFα) proteins are subunits of the HIF transcription factors, which regulate the expression of many genes associated with the response to hypoxia and proliferation. Under normoxic conditions the prolyl hydroxylase (PHD) proteins hydoxylate HIFα proteins, which creates a binding site recognized by the cullin RING ligase 2 (CRL2) – von Hippel Lindau tumor suppressor protein (VHL) E3 complex (CRL2^VHL). This leads to proteasomal degradation of HIFα proteins. The PHD proteins are ubiquitylated and degraded by the seven in absentia homologue (SIAH) RING finger E3s that are themselves transcriptionally upregulated by HIF transcription factors in response to hypoxia. The stability of HIFα proteins is also regulated by fumarate hydratase (FH) and succinate dehyrogenase (SDH), which are tumor suppressors associated with kidney cancer. The loss of FH and SDH results in the accumulation of fumarate and succinate, respectively, which competitively inhibit PHD activity and prevent hydroxylation and VHL-mediated degradation of HIFα proteins leading to inappropriate upregulation of hypoxia inducible genes. Figure reproduced with permission © Macmillan Publishers (2011).