The role of cullin 5-containing ubiquitin ligases
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Okumura et al. Cell Div (2016) 11:1 DOI 10.1186/s13008-016-0016-3
Open Access
REVIEW
The role of cullin 5‑containing ubiquitin ligases Fumihiko Okumura*, Akiko Joo‑Okumura, Kunio Nakatsukasa and Takumi Kamura*
Abstract The suppressor of cytokine signaling (SOCS) box consists of the BC box and the cullin 5 (Cul5) box, which interact with Elongin BC and Cul5, respectively. SOCS box-containing proteins have ubiquitin ligase activity mediated by the forma‑ tion of a complex with the scaffold protein Cul5 and the RING domain protein Rbx2, and are thereby members of the cullin RING ligase superfamily. Cul5-type ubiquitin ligases have a variety of substrates that are targeted for polyubiqui‑ tination and proteasomal degradation. Here, we review the current knowledge on the identification of Cul5 and the regulation of its expression, as well as the signaling pathways regulated by Cul5 and how viruses highjack the Cul5 system to overcome antiviral responses. Keywords: Ubiquitin, Cullin 5, Elongin, CRL complex
Identification and regulation of cullin 5 Cullin 5 (Cul5) was originally identified as a vasopressin-activated calcium-mobilizing (VACM-1) protein, an arginine vasopressin (AVP) receptor [1]. AVP is a nonapeptide that regulates body fluid and blood pressure homeostasis. VACM-1 is recognized as Cul5 because of its homology to the Caenorhabditis elegans gene Cul5 [2, 3]. Cul5 is expressed in many cells and organs, including endothelial cells, brain, kidney collecting tubule cells, and vascular endothelial cells [2, 4–6, 7]. Cul5 inhibits cyclic AMP production, and this effect is reversed by staurosporin, a protein kinase A (PKA) inhibitor, or by mutating S730A, the PKA-dependent phosphorylation site in the Cul5 sequence in COS-1 cells [8]. The inhibitory effect of Cul5 on AVP-stimulated cAMP production is enhanced by a protein kinase C inhibitor [8]. CUL-5 expression is downregulated in 82 % (41/50) of breast tumors compared with matched normal tissues [9]. Overexpression of Cul5 in T47D breast cancer cells decreases cell growth and mitogen activated protein kinase (MAPK) phosphorylation [10], and Cul5 overexpression downregulates
*Correspondence: [email protected]‑u.ac.jp; [email protected]‑u.ac.jp Division of Biological Science, Graduate School of Science, Nagoya University, Nagoya, Aichi 464‑8602, Japan
early growth response 1 (EGR-1) protein expression and upregulates Fas-L mRNA expression [10]. The regulation of both MAPK and EGR-1 pathways by 17β-estradiol led to the examination of estrogen-dependent T47D cell growth, which showed that Cul5 inhibits basal and 17β-estradiol-dependent cell growth and MAPK phosphorylation [11]. Resveratrol (trans-3,5,4′-trihydroxystilbene), which inhibits tumor initiation and promotion, is a natural component of the human diet, and its wide range of biological activities has been demonstrated in vivo and in vitro [12–15]. The antiproliferative effect of resveratrol is significantly enhanced by Cul5 overexpression in T47D cells [16]. The expression of Cul5
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