UBXD Proteins: A Family of Proteins with Diverse Functions in Cancer

Abstract

The UBXD family is a diverse group of UBX (ubiquitin-regulatory X) domain-containing proteins in mammalian cells. Members of this family contain a UBX domain typically located at the carboxyl-terminal of the protein. In contrast to the UBX domain shared by all members of UBXD family, the amino-terminal domains are diverse and appear to carry out different roles in a subcellular localization-dependent manner. UBXD proteins are principally associated with the endoplasmic reticulum (ER), where they positively or negatively regulate the ER-associated degradation machinery (ERAD). The distinct protein interaction networks of UBXD proteins allow them to have specific functions independent of the ERAD pathway in a cell type- and tissue context-dependent manner. Recent reports have illustrated that a number of mammalian members of the UBXD family play critical roles in several proliferation and apoptosis pathways dysregulated in selected types of cancer. This review covers recent advances that elucidate the therapeutic potential of selected members of the UBXD family that can contribute to tumor growth.

Keywords: UBXD family; animal models; apoptosis; cell proliferation; targeted therapy; tumor; xenografts.

Figure 1

Schematic domain structures of the UBXD proteins. Linear representations of the domain structures of the nine members of the UBXD protein family involved in diverse tumorigenic pathways. The ubiquitin-regulatory X (UBX) domain is located at the C-terminus of proteins and is a defining feature of the family. Diverse domains and their different combinations located at the N-terminus of proteins enable UBXD proteins to bind to selected partners/substrates and contribute to diverse functions in different cell compartments. PUG (PNGase/UBA or UBX) domain, also known as PUB domain, binds to p97 protein. The SEP domain is named for Saccharomyces cerevisiae Shp1, Drosophila melanogaster eyes closed gene (eyc), and vertebrate p47. UAS and UIM stand for FAS-associated factor 1 and Ubiquitin-Interacting Motif, respectively. UB1 and UB2 are ubiquitin homologous domain 1 and 2, respectively.

Figure 2

Overview of the UBXN2A binding partners which can mediate its tumor suppressor abilities. The presence of UBXN2A can inhibit mortalin-2 oncoprotein and prevent tumor formation by inducing apoptosis and/or and inhibiting cell growth, adhesion, and migration. Furthermore, UBXN2A can regulate the proteasomal degradation of CHIP’s substrates, including oncoproteins in cancer cells. Further studies will provide a better picture of the anti-cancer functions of UBXN2A and its potential therapeutic benefits.

Figure 3

Functions of three members of the UBXD protein family (UBXN1, P47, and FAF1) that are potentially involved in the prevention of cancer. It has been well established that aberrant regulation of nuclear factor-kappaB (NF-κB) and its downstream cascade are involved in several aspects of tumor progression as well as resistance to chemo- and radio-therapies. The NF-κB signaling pathway is regulated by a network of intermediate and adaptor proteins. UBXN1, p47, and FAF1 can target and inhibit several of these key regulatory proteins and block transcription of oncogenic genes activated by the NF-κB pathway. TNFα = tumor necrosis factor α, TNF-R1 = tumor necrosis factor receptor 1, TRADD = TNFR1-associated death domain protein. TRAF2 = tumor necrosis factor receptor-associated factor 2, NEMO = NF-κB essential modulator, IKKα and IKKβ = IκB kinase complex (IKK)-α and IκB kinase complex (IKK)-β, cIAP1 and cIAP2 = cellular inhibitor of apoptosis 1 and 2. The thin black arrow stands for the poly ubiquitination process. Initiation or activation is shown by thick black arrows and inhibition is shown by brown T-bars.

Figure 4

The UBXD family and cancer. UBXD family proteins are involved in a broad range of biological processes in normal and disease states, including cancers. Based on current literature, several members of the UBXD family contribute to oncogenic processes such as cell proliferation and apoptosis. A greater understanding of the interplay among UBXD family members, other binding partners, and regulators of tumorigenic pathways, particularly in animal models, is crucial for the design of a new generation of anti-cancer drugs targeting members of the UBXD family. Identification of the tumor-suppressing functions of UBXD proteins is important within a particular tissue or cell type. Targeting these novel tumor suppressor proteins can enhance the effectiveness of current treatment strategies without damaging normal cells. Initiation or activation is shown by arrows and inhibition is shown by brown T-bars. “?” = Further studies are needed.