CRL4B Catalyzes H2AK119 Monoubiquitination and Coordinates with PRC2 to Promote Tumorigenesis

Hu, Huili; Yang, Yang; Ji, Qinghong; Zhao, Wei; Jiang, Baichun; Liu, Ruiqiong; Yuan, Jupeng; Li, Qiao; Li, Xi; Zou, Yongxin; Shao, Changshun; Shang, Yongfeng; Wang, Yan; Gong, Yaoqin

doi:10.1016/j.ccr.2012.10.024

Cited by 138 publications

(196 citation statements)

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“…CRL4B has been shown to repress transcription in cooperation with the PRC2 complex (28). We then investigated whether CUL4B regulates the gene expression of Cav1.2 and AC6 through an epigenetic mechanism.…”

Section: Cul4b Ablation In Pancreatic δ Cells Other Than β Cells Causmentioning

confidence: 99%

“…Unlike CUL4A and other cullins, CUL4B harbors an N-terminal nuclear localization sequence that directs it to nucleus to regulate cell functions in an epigenetic manner (18,(25)(26)(27). Recently, we have shown that cullin 4B-RING E3 ligase (CRL4B) functions as a transcriptional corepressor by catalyzing H2AK119 ubiquitination (H2A119ub1) and coordinating with polycomb repressive complex 2 (PRC2) to regulate histone H3 lysine 27 (H3K27) trimethylation (28,29). Other studies have demonSomatostatin secreted by pancreatic δ cells mediates important paracrine interactions in Langerhans islets, including maintenance of glucose metabolism through the control of reciprocal insulin and glucagon secretion.…”

Section: Introductionmentioning

confidence: 99%

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A cullin 4B-RING E3 ligase complex fine-tunes pancreatic δ cell paracrine interactions

Cui

Yang

et al. 2017

Journal of Clinical Investigation

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Figure 1. CUL4B deficiency in pancreatic δ cells impairs glucose metabolism. (A and B)Western blots and quantitative data for CUL4A and CUL4B protein levels in islets from 12-week-old diabetic db/db mice and their heterozygous littermates (db/+). n = 6 mice per group. Representative Western blots from at least 3 independent experiments are shown. (C) Immunostaining for CUL4B (green) and somatostatin (SST, red) in pancreatic sections from db/db and db/+ mice. Scale bar: 100 μm. n = 6 mice per group; 4-7 random areas were selected from each islet section, and 10 sections were randomly selected from each mouse. Insulininduced decreases in blood glucose levels were significantly lower in Sst-Cre +/-Cul4b fl/Y mice than in their WT littermates, and they did not return to baseline levels at the 2-hour time point, whereas the levels of their WT littermates did (n = 9-11). *P < 0.05; **P < 0.01; ***P < 0.001. db/db mice were compared with their db/+ littermates, and Sst-Cre +/-Cul4b fl/Y mice were compared with their WT littermates. Error bars in F represent mean ± SD; other bars represent mean ± SEM. All data were analyzed using 1-way ANOVA. The Journal of Clinical Investigation R E S E A R C H A R T I C L E2 6 3 3 jci.orgVolume 127 Number 7 July 2017mental Figure 1E). Immunofluorescence also showed no significant differences in islet or β or δ cell numbers between +/-mice, the knockout mice exhibited increased glucose levels after 2 hours of feeding following a 16-hour fast ( Figure 1G). Accordingly, during a glucose tolerance test, the blood glucose levels of Sst-Cre +/-Cul4b fl/Y mice were 33% and 30% higher at 30 minutes and 120 minutes, respectively, than those of the control group consisting of both Sst-Cre +/-and Cul4b fl/Y mice ( Figure 1H). In addition, during the insulin tolerance test, the blood glucose levels of Sst-Cre +/-Cul4b fl/Y mice unexpectedly decreased more dramatically and rapidly than those of the Sst-Cre +/-control mice in response to insulin stimulation ( Figure 1I). Insulin and somatostatin content as well as kidney, brain, heart, liver, and stomach weights were not found to be significantly different between the mice was 140% and 40% higher than that of Sst-Cre +/-mice at 5 minutes and 60 minutes, respectively ( Figure 2H). In contrast to the results found for the Sst-Cre +/-Cul4b fl/Y mice, CUL4B defistrated that CRL4 ubiquitinates WD repeat-containing protein 5 (WDR5), a core subunit of H3K4 methyltransferase complexes, for degradation in the nucleus, thereby promoting increased H3K4 methylation levels (30). However, whether CUL4B or its E3 ligase complex CRL4B-PRC2 participates in the functioning or development of Langerhans islets has not been studied. In this study, we found that CUL4B expression levels are decreased in db/db mice. Therefore, we crossed mice expressing Cre under the insulin II promotor (Ins2-Cre) and mice expressing Cre under the somatostatin promoter (Sst-Cre) with Cul4b fl/fl mice to characterize CUL4B functions in specific cell types of the islet circuit. Although In...

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Section: Cul4b Ablation In Pancreatic δ Cells Other Than β Cells Causmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A cullin 4B-RING E3 ligase complex fine-tunes pancreatic δ cell paracrine interactions

Cui

Yang

et al. 2017

Journal of Clinical Investigation

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“…CUL4B ablation could block the degradation of WDR5, a core subunit of the histone H3 lysine 4 (H3K4) methyltransferase complex, and thus increase H3K4 trimethylation (H3K4me3) on some neuronal gene promoters, leading to their upregulation (Nakagawa and Xiong, 2011). Recently, we have shown that CRL4B functions as a transcriptional co-repressor of tumor suppressors by monoubiquitylating H2AK119 and coordinating with either the PRC2 complex or with DNA methyltransferase, HP1 and SUV39H1 to regulate histone methylation or DNA methylation (Hu et al, 2012;Yang et al, 2013). Here, we show that CUL4B depletion can inhibit cell proliferation owing to the upregulation of Cdkn1a and Cdkn1c.…”

Section: Introductionmentioning

confidence: 99%

“…CRL4 targets different substrates for proteasomal degradation or for protein modification, and thus regulates a broad variety of physiologically and developmentally controlled processes (Higa and Zhang, 2007). Although earlier studies focused on the redundant function and common substrates of members of the CUL4 family, CUL4B has been recently reported to function distinctly from CUL4A in transcriptional repression, neuronal gene regulation, response to reactive oxygen species (ROS) and microRNA regulation (Hu et al, 2012;Li et al, 2011;Nakagawa and Xiong, 2011;Zou et al, 2013). Although CUL4A has been proved to regulate the cell cycle by targeting CDT1 and CKIs such as p21 and p27 (encoded by CDKN1B) for proteolysis in cultured cells, it seems to be dispensable for embryonic development (Abbas et al, 2008;Hu et al, 2004;Li et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

CRL4B interacts and coordinates with SIN3A/HDAC complex to repress CDKN1A in driving cell cycle progression

Yang

et al. 2014

Journal of Cell Science

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CUL4B, a scaffold protein that assembles the CRL4B ubiquitin ligase complex, participates in the regulation of a broad spectrum of biological processes. Here, we demonstrate a crucial role of CUL4B in driving cell cycle progression. We show that loss of CUL4B results in a significant reduction in cell proliferation and causes G1 cell cycle arrest, accompanied by the upregulation of the cyclindependent kinase (CDK) inhibitors (CKIs) p21 and p57 (encoded by CDKN1A and CDKN1C, respectively). Strikingly, CUL4B was found to negatively regulate the function of p21 through transcriptional repression, but not through proteolysis. Furthermore, we demonstrate that CRL4B and SIN3A-HDAC complexes interact with each other and co-occupy the CDKN1A and CDKN1C promoters. Lack of CUL4B led to a decreased retention of SIN3A-HDAC components and increased levels of acetylated H3 and H4. Interestingly, the ubiquitylation function of CRL4B is not required for the stable retention of SIN3A-HDAC on the promoters of target genes. Thus, in addition to directly contributing to epigenetic silencing by catalyzing H2AK119 monoubiquitylation, CRL4B also facilitates the deacetylation function of SIN3A-HDAC. Our findings reveal a coordinated action between CRL4B and SIN3A-HDAC complexes in transcriptional repression.

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“…2008) and CRL4B RBBP4/7 (Hu et al . 2012). Consistent with the function of these six ubiquitin ligase complexes as transcriptional repressors, monoubiquitylated H2A inhibits transcription by several mechanisms including down‐regulation of methylation of histone H3 at lysine 4 (H3K4) (Nakagawa et al .…”

Section: Histone Monoubiquitylation and Transcriptional Regulationmentioning

confidence: 99%

Protein monoubiquitylation: targets and diverse functions

Nakagawa

Nakayama

2015

Genes to Cells

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Ubiquitin is a 76‐amino acid protein whose conjugation to protein targets is a form of post‐translational modification. Protein ubiquitylation is characterized by the covalent attachment of the COOH‐terminal carboxyl group of ubiquitin to an amino group of the substrate protein. Given that the NH2‐terminal amino group is usually masked, internal lysine residues are most often targeted for ubiquitylation. Polyubiquitylation refers to the formation of a polyubiquitin chain on the substrate as a result of the ubiquitylation of conjugated ubiquitin. The structures of such polyubiquitin chains depend on the specific lysine residues of ubiquitin targeted for ubiquitylation. Most of the polyubiquitin chains other than those linked via lysine‐63 and methionine‐1 of ubiquitin are recognized by the proteasome and serve as a trigger for substrate degradation. In contrast, polyubiquitin chains linked via lysine‐63 and methionine‐1 serve as a binding platform for proteins that function in immune signal transduction or DNA repair. With the exception of a few targets such as histones, the functions of protein monoubiquitylation have remained less clear. However, recent proteomics analysis has shown that monoubiquitylation occurs more frequently than polyubiquitylation, and studies are beginning to provide insight into its biologically important functions. Here, we summarize recent findings on protein monoubiquitylation to provide an overview of the targets and molecular functions of this modification.

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CRL4B Catalyzes H2AK119 Monoubiquitination and Coordinates with PRC2 to Promote Tumorigenesis

Cited by 138 publications

References 42 publications

A cullin 4B-RING E3 ligase complex fine-tunes pancreatic δ cell paracrine interactions

A cullin 4B-RING E3 ligase complex fine-tunes pancreatic δ cell paracrine interactions

CRL4B interacts and coordinates with SIN3A/HDAC complex to repress CDKN1A in driving cell cycle progression

Protein monoubiquitylation: targets and diverse functions

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