RBX1

What is RBX1 Protein?

RBX1 gene (ring-box 1) is a protein coding gene which situated on the long arm of chromosome 22 at locus 22q13. RBX1 is a protein that contains a RING finger-like domain. As a key component of the SCF (Skp1-Cullin-F-box) E3 ubiquitin ligase complex, it is involved in ubiquitination of a variety of proteins involved in cell cycle progression, signal transduction, transcription, and nucleotide excision repair of transcription coupling. RBX1 promotes the ubiquitination of target proteins by interacting with cullin proteins and recruiting the E2 ubiquitin-binding enzyme CDC34, which then marks these proteins for proteasome degradation. The RBX1 protein is consisted of 108 amino acids and RBX1 molecular weight is approximately 12.3 kDa.

What is the Function of RBX1 Protein?

RBX1 is an E3 ubiquitin ligase that facilitates the transfer of ubiquitin from an E2 ubiquitin-conjugating enzyme to specific target proteins, marking them for degradation by the 26S proteasome. By mediating the ubiquitination of target proteins, RBX1 contributes to the regulation of various cellular processes, including cell cycle progression, signal transduction, transcription, and DNA repair, through the degradation of short-lived regulatory proteins. RBX1 is involved in controlling numerous cellular processes because of its role in the SCF E3 ligase complex, which is responsible for the timely degradation of many key regulatory proteins. RBX1 is essential during mouse embryonic development, and its targeted disruption can cause embryonic lethality due to hypoproliferation as a result of p27 accumulation.

RBX1 Related Signaling Pathway

In specific tumor cells, such as uveal melanoma (UVM) cells, RBX1 is thought to regulate the expression of immune-related genes via the STAT1 signaling pathway. STAT1 (Signal Transducer and Activator of Transcription 1) is a key transcription factor in the JAK/STAT signaling pathway, which is involved in the regulation of various immune responses. Under the action of RBX1, the expression level of STAT1 and its downstream CXC chemokine ligand 9 (CXCL9) and CXCL10 may be affected. CXCL9 and CXCL10 are important chemokines that play a key role in mediating T lymphocyte migration.

Fig1. A working model for RBX1 targeting. (Lijun Jia, 2009)

RBX1 Related Diseases

The abnormal function of RBX1 is associated with a variety of diseases, especially closely related to the occurrence and development of tumors, such as uveal melanoma. In addition, the role of RBX1 in multiple myeloma (MM) has also received attention, and studies have found that RBX1 induces drug resistance in MM cells by inhibiting p27. Abnormal expression of RBX1 is also associated with other types of tumors, including liver, stomach, esophageal, breast, bladder, lung, and colon cancers, and its expression levels are associated with poor clinical outcomes. In addition, RBX1 is involved in the maintenance of regulatory T cells (Treg cells), whose function is essential for the immunosuppressive activity of Treg cells. The absence of RBX1 will cause the statical subsets of Treg cells to fail to differentiate into effector subsets, and affect the immunosuppressive function of Treg cells.

Case Study 1: Ji Jiang, 2018

Activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant response signaling pathway is a major mechanism for the cellular defense against oxidative stress. Arsenite, a widespread contaminant in drinking water, is known to induce oxidative stress and activate the Nrf2-dependent signaling pathway through the stabilization of the Nrf2 protein by inhibiting its ubiquitination via the Cul3-Rbx1-Keap1 (cullin 3, RING-box 1, and Kelch-like ECH-associated protein 1) E3 ubiquitin ligase, and its degradation by the 26S proteasome, though the underlying mechanism, remains elusive. In the present study, researchers demonstrated that arsenite could bind to the RING finger domain of Rbx1 in vitro and in cells, which led to the suppression of Cul3-Rbx1 E3 ubiquitin ligase activity, thereby impairing the Nrf2 ubiquitination and activating the Nrf2-induced antioxidant signaling pathway.

Fig1. UV absorption spectrum of the RING finger peptide of Rbx1.

Fig2. Streptavidin agarose affinity pull-down assay indicating the interaction between As3+ and Rbx1.

Case Study 2: Jingyang Zhang, 2017

Recent reports showed that regulator of Cullins-1 (ROC1) play an important role in tumor progression in a tumor-specific manner. However, the role and mechanism of ROC1 in esophageal cancer remains elusive. Here researchers demonstrated that ROC1 was overexpressed in esophageal squamous cell carcinomas, which was positive associated with poor prognosis of esophageal cancer patients. ROC1 knockdown significantly inhibited the growth of esophageal cancer cells in vitro and in vivo. Mechanistically, ROC1 silencing induced G2 cell cycle arrest and triggered apoptosis by accumulating the pro-apoptotic protein NOXA. Consistently, the downregulation of NOXA expression via siRNA substantially attenuated apoptosis induced by ROC1 silencing.

Fig3. Western blotting analysis to determine the expression of ROC1 in ESCC tissues and adjacent esophageal tissues.

Fig4. Proteins extracted from tumor tissues were analyzed by western blotting.

RBX1 has several biochemical functions, for example, NEDD8 transferase activity,cullin family protein binding,ligase activity. Some of the functions are cooperated with other proteins, some of the functions could acted by RBX1 itself. We selected most functions RBX1 had, and list some proteins which have the same functions with RBX1. You can find most of the proteins on our site.

RBX1 has direct interactions with proteins and molecules. Those interactions were detected by several methods such as yeast two hybrid, co-IP, pull-down and so on. We selected proteins and molecules interacted with RBX1 here. Most of them are supplied by our site. Hope this information will be useful for your research of RBX1.

CUL1;CUL4B