The functions and properties of cullin-5, a potential therapeutic target for cancers

Abstract

Cullin-5 (CUL5), a scaffold protein in active cullin-RING ubiquitin ligase (CRL) complexes, is a member of the cullin family of proteins. The CUL5-type ubiquitin ligase can target multiple proteins involved in ubiquitination and proteasome degradation. CUL5 plays positive roles in regulating cell growth, proliferation and physiological and other processes in the human body. It has been found that the expression of CUL5 is significantly downregulated in various cancer cells, which affects the course of the cancers. Here, we reviewed the current data on the expression and role of CUL5 in both normal and cancer cells, its possible mechanisms, and its potential as a therapeutic target for cancers.

Keywords: Cullin-5; cancer; microRNAs; regulation; therapeutics; ubiquitin.

Figure 1

The structure of CRL5.CUL5 serves as a scaffold and is the central component of CRL5. The NTD of CUL5 is linked to the SOCS box protein via the adaptor complex Elongin BC. The CTD binds to Rbx2, forming the CRL5 complex (SOCS-Elongin BC-CUL5-Rbx2). The CRL5 complex belongs to the E3 ubiquitin ligase family and can recruit E2 ubiquitin conjugating enzymes. RBX2 participates in the binding of E2 enzymes. The E2 enzyme is bound to activated ubiquitin, and under the action of CRL5, ubiquitin is transferred to the substrate to form the ubiquitin chain. Subsequently, the substrate tagged by the ubiquitin chain is recognized and degraded by the proteasome.

Figure 2

The main functions and mechanism of CUL5 in normal cells. CUL5 plays an important role in normal cell activities. CUL5, along with a SOCS box protein, Elongin BC and Rbx2, form the CRL5 complex and recruit the E2 enzyme. Then, the CRL5-E2 complex ubiquitinates and degrades componentsassociated with cellular activities, such as Dab-1, pYCas, Rpb1, AQP-1/2, DEPTOR, DDA3, and β-TrCP1. The degradation of key components alters or affects downstream signaling pathways and further regulates cell migration, transcription, autophagy and proliferation. Meanwhile, CUL5 can directly decrease the activity of AC and regulate the phosphorylation process of MAPK to affect cell proliferation. In addition, CUL5 can be inhibited by AMBRA1.

Figure 3

The expression of the CUL5 gene regulated by miRNAs. MiRNAs are involved in various types of cancers and malignancies. MiR-19a/b inhibits the expression of the CUL5 gene and is associated with gastric cancer and cervical cancer. Simultaneously, miR-145, miR-182, and miR-27a also inhibit the CUL5 gene and are related to HCC (associated with HBV infection), endometrial adenocarcinoma, and ovarian cancer, respectively. Conversely, the expression of the CUL5 gene can be promoted by miR-7, which is related to HCC development (not associated with HBV infection). Moreover, the chromosome region 11q22-q23 also promotes the expression of the CUL5 gene.