The functional analysis of Cullin 7 E3 ubiquitin ligases in cancer

Abstract Cullin (CUL) proteins have critical roles in development and cancer, however few studies on CUL7 have been reported due to its characteristic molecular structure. CUL7 forms a complex with the ROC1 ring finger protein, and only two F-box proteins Fbxw8 and Fbxw11 have been shown to bind to CUL7. Interestingly, CUL7 can interact with its substrates by forming a novel complex that is independent of these two F-box proteins. The biological implications of CUL-ring ligase 7 (CRL7) suggest that the CRL7 may not only perform a proteolytic function but may also play a non-proteolytic role. Among the existing studied CRL7-based E3 ligases, CUL7 exerts both tumor promotion and suppression in a context-dependent manner. Currently, the mechanism of CUL7 in cancer remains unclear, and no studies have addressed potential therapies targeting CUL7. Consistent with the roles of the various CRL7 adaptors exhibit, targeting CRL7 might be an effective strategy for cancer prevention and treatment. We systematically describe the recent major advances in understanding the role of the CUL7 E3 ligase in cancer and further summarize its potential use in clinical therapy.

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Role of a novel pathogen-induced pepper C3–H–C4 type RING-finger protein gene, CaRFP1, in disease susceptibility and osmotic stress tolerance

Plant Molecular Biology ◽

10.1007/s11103-006-9110-2 ◽

2006 ◽

Vol 63 (4) ◽

pp. 571-588 ◽

Cited By ~ 41

Author(s):

Jeum Kyu Hong ◽

Hyong Woo Choi ◽

In Sun Hwang ◽

Byung Kook Hwang

Keyword(s):

Osmotic Stress ◽

Stress Tolerance ◽

Disease Susceptibility ◽

Protein Gene ◽

Ring Finger ◽

Ring Finger Protein ◽

Osmotic Stress Tolerance ◽

Finger Protein

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Arkadia (RING Finger Protein 111) Mediates Sumoylation-Dependent Stabilization of Nrf2 Through K48-Linked Ubiquitination

Cellular Physiology and Biochemistry ◽

10.1159/000488475 ◽

2018 ◽

Vol 46 (1) ◽

pp. 418-430 ◽

Cited By ~ 5

Author(s):

Deneshia J. McIntosh ◽

Treniqka S. Walters ◽

Ifeanyi J. Arinze ◽

Jamaine Davis

Keyword(s):

Gene Transcription ◽

Ring Finger ◽

Nuclear Body ◽

Promyelocytic Leukemia ◽

Heme Oxygenase 1 ◽

Ring Finger Protein ◽

Whole Cell ◽

Cell Lysates ◽

Finger Protein

Background/Aims: The transcription factor Nrf2 is a master regulator of the antioxidant defense system, protecting cells from oxidative damage. We previously reported that the SUMO-targeted E3 ubiquitin ligase (STUbL), RING finger protein 4 (RNF4) accelerated the degradation rate of Nrf2 in promyelocytic leukemia-nuclear body (PML-NB)-enriched fractions and decreased Nrf2-mediated gene transcription. The mechanisms that regulate Nrf2 nuclear levels are poorly understood. In this study, we aim to explore the role of the second mammalian STUbL, Arkadia/RNF111 on Nrf2. Methods: Arkadia mediated ubiquitination was detected using co-immunoprecipitation assays in which whole cell lysates were immunoprecipated with anti-Nrf2 antibody and Western blotted with anti-hemagglutinin (HA) antibody or anti-Lys-48 ubiquitin-specific antibody. The half-life of Nrf2 was detected in whole cell lysates and promyelocytic leukemia-nuclear body enriched fractions by cycloheximide-chase. Reporter gene assays were performed using the antioxidant response element (ARE)-containing promoter Heme oxygenase-1 (HO-1). Results: We show that Arkadia/RNF111 is able to ubiquitinate Nrf2 resulting in the stabilization of Nrf2. This stabilization was mediated through Lys-48 ubiquitin chains, contrary to traditionally degradative role of Lys-48 ubiquitination, suggesting that Lys-48 ubiquitination of Nrf2 protects Nrf2 from degradation thereby allowing Nrf2-dependent gene transcription. Conclusion: Collectively, these findings highlight a novel mechanism to positively regulate nuclear Nrf2 levels in response to oxidative stress through Arkadia-mediated K48-linked ubiquitination of Nrf2.

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Structural basis for role of ring finger protein RNF168 RING domain

Cell Cycle ◽

10.4161/cc.23104 ◽

2013 ◽

Vol 12 (2) ◽

pp. 312-321 ◽

Cited By ~ 8

Author(s):

Xiaoqin Zhang ◽

Jie Chen ◽

Minhao Wu ◽

Huakai Wu ◽

Aloysius Wilfred Arokiaraj ◽

...

Keyword(s):

Ring Finger ◽

Ring Domain ◽

Structural Basis ◽

Ring Finger Protein ◽

Finger Protein

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Screen for multi-SUMO–binding proteins reveals a multi-SIM–binding mechanism for recruitment of the transcriptional regulator ZMYM2 to chromatin

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1509716112 ◽

2015 ◽

Vol 112 (35) ◽

pp. E4854-E4863 ◽

Cited By ~ 21

Author(s):

Elisa Aguilar-Martinez ◽

Xi Chen ◽

Aaron Webber ◽

A. Paul Mould ◽

Anne Seifert ◽

...

Keyword(s):

Transcriptional Control ◽

Ring Finger ◽

Binding Activity ◽

Ring Finger Protein ◽

E3 Ligases ◽

Binding Partner ◽

Finger Protein ◽

Sumo Binding Proteins ◽

Nuclear Processes ◽

Regulatory Event

Protein SUMOylation has emerged as an important regulatory event, particularly in nuclear processes such as transcriptional control and DNA repair. In this context, small ubiquitin-like modifier (SUMO) often provides a binding platform for the recruitment of proteins via their SUMO-interacting motifs (SIMs). Recent discoveries point to an important role for multivalent SUMO binding through multiple SIMs in the binding partner as exemplified by poly-SUMOylation acting as a binding platform for ubiquitin E3 ligases such as ring finger protein 4. Here, we have investigated whether other types of protein are recruited through multivalent SUMO interactions. We have identified dozens of proteins that bind to multi-SUMO platforms, thereby uncovering a complex potential regulatory network. Multi-SUMO binding is mediated through multi-SIM modules, and the functional importance of these interactions is demonstrated for the transcriptional corepressor ZMYM2/ZNF198 where its multi-SUMO–binding activity is required for its recruitment to chromatin.

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