Atypical ubiquitin ligase RNF31: the nuclear factor modulator in breast cancer progression

Abstract

Breast cancer causes the No.1 women cancer prevalence and the No.2 women cancer mortality worldwide. Nuclear receptor/transcriptional factor signaling is aberrant and plays important roles in breast cancer pathogenesis and evolution, such as estrogen receptor α (ERα/ESR1), tumor protein p53 (p53/TP53) and Nuclear factor kappa B (NFκB). About 60-70 % of breast tumors are ERα positive, while approximate 70 % of breast tumors are P53 wild type. Recent studies indicate that nuclear receptors/transcriptional factors could be tightly controlled through protein post-translational modification.The nuclear receptors/transcriptional factors could endure several types of modifications, including phosphorylation, acetylation and ubiquitination. Compared with the other two types of modifications, ubiquitination was mostly linked to protein degradation process, while few researches focused on the functional changes of the target proteins. Until recent years, ubiquitination process is no longer regarded as merely a protein degradation process, but aslo treated as one kind of modification signal.As an atypical E3 ubiquitin ligase, RNF31 was previously found to facilitate NFκB signaling transduction through linear ubiquitination on IKKγ(IκB kinase γ). Our previous studies showed important regulatory functions of RNF31 in controlling important oncogenic pathways in breast cancer, such as ERα and p53. This review highlights recent discoveries on RNF31 functions in nuclear factor modifications, breast cancer progression and possible therapeutic inhibitors targeting RNF31.

Keywords: Breast cancer; Estrogen; RNF31; Ubiquitin ligase.

Fig. 1

RNF31 protein domain structure. PUB domain, putative ubiquitin binding domain; ZNF-RBZ domain, Zinc finger domain in Ran-binding proteins and other proteins; UBA domain, ubiquitin binding associated domain; RING-IBR-RING domain, ring finger domain-in between RING-ring finger domain

Fig. 2

The proposed model for RNF31 effect on ERα signaling in breast cancer. RNF31 interacts with ERα and increases its stability possibility through the mono-ubiquitination manner. The stabilized ERα protein will enhance the estrogen dependent signaling transduction

Fig. 3

The known ERα protein acetylation, sumoylation and ubiquitination sites and their corresponding enzymes. The Activator Function 1 (AF1) domain at the N-terminal of the ERα protein can transactivate transcription in the absence of ligand binding. The DNA-binding domain (DBD) binds to estrogen response elements (EREs) in DNA. The AF2 domain is the ligand-dependent transactivation domain. As part of its transactivation function, the AF2 domain also binds to several co-activators and co-repressors of ERα

Fig. 4

P53 protein domain structure. The N-terminal part amino acids 1–42, constitutes the transactivation domain. The proline-rich domain, from amino acid 42 to amino acid 100, is proven necessary for p53 dependent apoptosis and cell cycle arrest. The DBD (DNA binding domain) is rich in arginine and related to transcriptional activity. The protein domain from amino acid 305 to amino acid 322 includes the nuclear localization domain. The domain from amino acid 340 to amino acid 351 includes the nuclear exclusion domain. In addition, the protein domain from amino acid 326 to amino acid 356 corresponds to the tetramerization domain. The C-terminal domain from amino acid 364 to amino acid 393 is required for DNA binding capability and DNA damage response

Fig. 5

The regulatory effect of RNF31 and other E3 ligases on P53. RNF31 interacts with P53/MDM2 complex and facilitates P53 degradation in MDM2 dependent manner