Nuclear cereblon modulates transcriptional activity of Ikaros and regulates its downstream target, enkephalin, in human neuroblastoma cells

Wada, Takeyoshi; Asahi, Toru; Sawamura, Naoya

doi:10.1016/j.bbrc.2016.06.091

Cited by 13 publications

(11 citation statements)

References 38 publications

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“…Degradation of IKZF1 and IKZF3 is therapeutically exploited in the treatment of hematological malignancies. This clinically relevant degradation through cereblon occurs in the nucleus 51 . Our results argue that this activity is mediated by CUL4B, not CUL4A.…”

Section: Discussionmentioning

confidence: 99%

The ubiquitin ligase Cullin-1 associates with chromatin and regulates transcription of specific c-MYC target genes

Sweeney

Iakova

Maneix

et al. 2020

Sci Rep

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Transcription is regulated through a dynamic interplay of DNA-associated proteins, and the composition of gene-regulatory complexes is subject to continuous adjustments. Protein alterations include post-translational modifications and elimination of individual polypeptides. Spatially and temporally controlled protein removal is, therefore, essential for gene regulation and accounts for the short half-life of many transcription factors. The ubiquitin-proteasome system is responsible for siteand target-specific ubiquitination and protein degradation. Specificity of ubiquitination is conferred by ubiquitin ligases. Cullin-RING complexes, the largest family of ligases, require multi-unit assembly around one of seven cullin proteins. To investigate the direct role of cullins in ubiquitination of DNAbound proteins and in gene regulation, we analyzed their subcellular locations and DNA-affinities. We found CUL4A and CUL7 to be largely excluded from the nucleus, whereas CUL4B was primarily nuclear. CUL1,2,3, and 5 showed mixed cytosolic and nuclear expression. When analyzing chromatin affinity of individual cullins, we discovered that CUL1 preferentially associated with active promoter sequences and co-localized with 23% of all DNA-associated protein degradation sites. CUL1 co-distributed with c-MYC and specifically repressed nuclear-encoded mitochondrial and splicing-associated genes. These studies underscore the relevance of spatial control in chromatin-associated protein ubiquitination and define a novel role for CUL1 in gene repression. Mammalian gene expression follows oscillatory patterns, caused by alternating binding of transcriptional activators and repressors to specific DNA elements 1. The exchange of regulators during such cycles is partially accomplished through protein removal and subsequent degradation by the ubiquitin-proteasome system 2. Therefore, it is not surprising that transcription factors and their co-regulators are among the most short-lived proteins 3. However, the specific factors that trigger the removal of chromatin-associated proteins, and the genomic locations of degradation remain ill-defined 4. The ubiquitin-proteasome system is a multi-enzyme cascade that triggers the covalent attachment of ubiquitin polypeptides to target proteins. Ubiquitination can impact protein function and trafficking, or mark proteins for proteasomal digestion. The ubiquitin-proteasome system is responsible for the removal of most nuclear and cytosolic proteins. This pathway regulates transcription directly through epigenetic ubiquitination and through poly-ubiquitination that can lead to the removal of DNA-associated proteins 5,6. Furthermore, earlier work by our group and others indicates that the turnover of transcriptional regulators is site-selective and specific to some of the DNA regions to which these proteins are bound. Nuclear degradation by the ubiquitin-proteasome system is therefore not only target protein-selective, but also displays spatial specificity 7,8 .

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Section: Discussionmentioning

confidence: 99%

The ubiquitin ligase Cullin-1 associates with chromatin and regulates transcription of specific c-MYC target genes

Sweeney

Iakova

Maneix

et al. 2020

Sci Rep

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“…The results derived from immunohistochemistry staining ( Figure 6 ) indicate that CRBN is located in not only cytosol, but also in nucleus, suggesting that CRBN may have multiple functions. In fact, it has been found that nuclear CRBN modulates transcriptional activity of ikaros and regulates its downstream target encephalin [ 28 ], whereas mitochondrial CRBN functions as a Lon protease [ 29 ]. Thus, development of highly specific mouse mAbs against human CRBN may provide a tool to determine: (1) the levels of CRBN; (2) the localization of CRBN; (3) the functional roles of CRBN in each individual cellular organelle; and (4) especially to confirm the relationship between CRBN expression and IMiD sensitivity or between CRBN expression and proteasome inhibitor sensitivity in patients with MM.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, CRBN has been found to be located in cytoplasm and nucleus [ 24 , 25 , 27 ]. It has been found that: (1) nuclear CRBN modulates transcriptional activity of ikaros and regulates its downstream target encephalin [ 28 ]; (2) mitochondrial CRBN functions as a Lon protease [ 29 ]. Thus, clinical value of CRBN measurement to determine the relationship between CRBN expression and IMiD sensitivity or between CRBN expression and proteasome inhibitor sensitivity is a very important issue, whereas determining CRBN subcellular localization is another important issue for finding out CRBN function in each individual cellular organelle.…”

Section: Introductionmentioning

confidence: 99%

Mouse Monoclonal Antibodies Generated from Full Length Human Cereblon: Detection of Cereblon Protein in Patients with Multiple Myeloma

Chang

Hou

et al. 2017

IJMS

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Immunomodulatory drugs (IMiDs) are profoundly active compounds in the treatment of patients with multiple myeloma (MM). However, despite the fact that treatment with IMiDs has dramatically improved survival for patients with MM, the majority of MM patients develop IMiDs resistance over time. We have found that expression of functional cereblon is required for IMiDs′ action. In addition, it has been reported that cells expressing high levels of cereblon are resistant to proteasome inhibitor, implying that patients with high levels of cereblon should be resistant to proteasome inhibitor. If the above conclusions are correct, cereblon could be considered as a biomarker to determine which standard regimens should be used to treat patients with MM. Unfortunately, the conclusions mentioned above have not been clinically confirmed. In order to confirm these conclusions, we have generated three highly specific mouse monoclonal antibodies (mAbs) against full-length human cereblon. These mAbs can be used to do western blot, immunoprecipitation and immunohistochemistry staining. In addition, their epitopes have been precisely determined and the peptides covering their epitopes completely blocked the antibody binding to cereblon in western blot analysis or in immunohistochemistry staining of MM patients′ specimens.

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“…CRBN, a 442-amino acid protein with multifunction, locates in the cytoplasm, nucleus, and peripheral membrane of the human brain and other tissues [ 5 ]. The diverse roles of CRBN on cell metabolism and disease genesis have been extensively studied.…”

Section: Crbn Expression Affects Cell Metabolism and Disease Genermentioning

confidence: 99%

Cereblon: A Protein Crucial to the Multiple Functions of Immunomodulatory Drugs as well as Cell Metabolism and Disease Generation

Shi

Chen

2017

Journal of Immunology Research

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It is well known that cereblon is a key protein in autosomal recessive nonsyndromic mental retardation. Studies have reported that it has an intermediary role in helping immunomodulatory drugs perform their immunomodulatory and tumoricidal effects. In addition, cereblon also regulates the expression, assembly, and activities of other special proteins related to cell proliferation and metabolism, resulting in the occurrence and development of metabolic diseases. This review details the multiple functions of cereblon and the underlying mechanisms. We also put forward some unsolved problems, including the intrinsic mechanism of cereblon function and the possible regulatory mechanisms of its expression.

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Nuclear cereblon modulates transcriptional activity of Ikaros and regulates its downstream target, enkephalin, in human neuroblastoma cells

Cited by 13 publications

References 38 publications

The ubiquitin ligase Cullin-1 associates with chromatin and regulates transcription of specific c-MYC target genes

The ubiquitin ligase Cullin-1 associates with chromatin and regulates transcription of specific c-MYC target genes

Mouse Monoclonal Antibodies Generated from Full Length Human Cereblon: Detection of Cereblon Protein in Patients with Multiple Myeloma

Cereblon: A Protein Crucial to the Multiple Functions of Immunomodulatory Drugs as well as Cell Metabolism and Disease Generation

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