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https://www.readbyqxmd.com/read/29748389/cereblon-suppresses-lipopolysaccharide-induced-inflammatory-response-through-promoting-the-ubiquitination-and-degradation-of-c-jun
#1
Jing Yang, Min Huang, Liang Zhou, Xian He, Xiaogang Jiang, Yang Zhang, Guoqiang Xu
Chronic inflammation is associated with multiple human disorders such as rheumatoid arthritis, metabolic diseases, and neurodegenerative diseases. Therefore, alleviation of inflammation induced by environment stimuli is important for disease prevention or treatment. Cereblon (CRBN) functions as a substrate receptor of the cullin-4 RING E3 ligase to mediate protein ubiquitination and degradation. Although it has been reported that CRBN reduces the inflammatory response through its non-enzymatic function, its role as a substrate receptor of the E3 ligase is not explored in mediating this process...
May 10, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29730289/aerobic-exercise-training-decreases-cereblon-and-increases-ampk-signaling-in-the-skeletal-muscle-of-stz-induced-diabetic-rats
#2
Jeong Rim Ko, Dae Yun Seo, Se Hwan Park, Hyo Bum Kwak, Min Kim, Kyung Soo Ko, Byoung Doo Rhee, Jin Han
Cereblon (CRBN) has been reported as a negative regulator of adenosine monophosphate-activated protein kinase (AMPK). Aerobic exercise training has been shown to increase AMPK, which resulted in glucose regulation in skeletal muscle. However, the expression level of CRBN and its interaction with the physiological modulation of glucose are still unclear. Male Sprague-Dawley rats (5-week-old, n = 18) were assigned to control, streptozotocin (STZ, 65 mg/kg)-induced diabetic group, and STZ + exercise (STZ + EXE) group with six rats in each group...
May 3, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29729093/baicalein-inhibits-proliferation-of-myeloma-u266-cells-by-downregulating-ikzf1-and-ikzf3
#3
Xiao-Ping Liu, Li He, Qiu-Ping Zhang, Xian-Tao Zeng, Shang-Qin Liu
BACKGROUND Baicalein can suppress the growth of multiple tumors, including multiple myeloma (MM), but the exact mechanisms remains elusive. Here, we investigated the exact mechanisms of the anti-myeloma activity of baicalein. MATERIAL AND METHODS Proliferation and rates of apoptosis of myeloma U266 cells exposed to baicalein were detected. Microarray, polymerase chain reaction (PCR) assay, and Western blot analysis were applied to evaluate the mRNA and protein levels of associated molecules. Survival analysis of IKZF1 and IKZF3 was conducted as well...
May 5, 2018: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
https://www.readbyqxmd.com/read/29718735/expression-of-crbn-ikzf1-and-ikzf3-does-not-predict-lenalidomide-sensitivity-and-mutations-in-the-cereblon-pathway-are-infrequent-in-multiple-myeloma
#4
Konstantinos Dimopoulos, Helga Fibiger Munch-Petersen, Christian Winther Eskelund, Lene Dissing Sjö, Elisabeth Ralfkiaer, Peter Gimsing, Kirsten Grønbaek
The immunomodulatory drug thalidomide, and its analogs, lenalidomide, and pomalidomide (IMiDs), have become essential components of the standard treatment for multiple myeloma (MM), and have led to significant improvement of survival in patients with this devastating disease. Cereblon (CRBN), the direct target of IMiDs, has been proposed as a predictive biomarker of response to IMiDs. Using standard immunohistochemistry in formalin-fixed paraffin embedded (FFPE) bone marrow samples of 23 patients treated with a lenalidomide-containing regimen, we found that the malignant plasma cells of all the patients stained positive for CRBN, IKZF1, and IKZF3, regardless of sensitivity to IMiDs...
May 2, 2018: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/29545347/a-novel-nano-immunoassay-method-for-quantification-of-proteins-from-cd138-purified-myeloma-cells-biological-and-clinical-utility
#5
Irena Misiewicz-Krzeminska, Luis Antonio Corchete, Elizabeta A Rojas, Joaquín Martínez-López, Ramón García-Sanz, Albert Oriol, Joan Bladé, Juan-José Lahuerta, Jesús San Miguel, María-Victoria Mateos, Norma C Gutiérrez
Protein analysis in bone marrow samples from patients with multiple myeloma has been limited by the low concentration of proteins obtained after CD138+ cell selection. A novel approach based on capillary nano-immunoassay could make it possible to quantify dozens of proteins from each myeloma sample in an automated manner. Here we present a method for the accurate and robust quantification of the expression of multiple proteins extracted from CD138-purified multiple myeloma samples frozen in RLT Plus buffer, which is commonly used for nucleic acid preservation and isolation...
May 2018: Haematologica
https://www.readbyqxmd.com/read/29530986/cereblon-maintains-synaptic-and-cognitive-function-by-regulating-bk-channel
#6
Tae-Yong Choi, Seung-Hyun Lee, Yoon-Jung Kim, Jae Ryul Bae, Kwang Min Lee, Youhwa Jo, Soo-Jeong Kim, A-Ram Lee, Sekyu Choi, La-Mee Choi, Sunhoe Bang, Mi-Ryoung Song, Jongkyeong Chung, Kyung Jin Lee, Sung Hyun Kim, Chul-Seung Park, Se-Young Choi
Mutations in the cereblon ( CRBN ) gene cause human intellectual disability, one of the most common cognitive disorders. However, the molecular mechanisms of CRBN -related intellectual disability remain poorly understood. We investigated the role of CRBN in synaptic function and animal behavior using male mouse and Drosophila models. Crbn knock-out (KO) mice showed normal brain and spine morphology as well as intact synaptic plasticity; however, they also exhibited decreases in synaptic transmission and presynaptic release probability exclusively in excitatory synapses...
April 4, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/29496670/imid-compounds-affect-cd34-cell-fate-and-maturation-via-crbn-induced-ikzf1-degradation
#7
Shirong Li, Jing Fu, Hui Wang, Huihui Ma, Xiaoming Xu, Yong-Guang Yang, Shixian Deng, Markus Y Mapara, Suzanne Lentzsch
We have previously shown that immunomodulatory drug (IMiD) compounds induce a shift into immature myeloid precursors with a maturational arrest and subsequent neutropenia. The mechanism of action is unknown. Here we found that IMiD compounds cause selective ubiquitination and degradation of the transcription factor IKZF1 in CD34+ cells by the Cereblon (CRBN) E3 ubiquitin ligase. Loss of IKZF1 is associated with a decrease of the IKZF1-dependent transcription factor PU.1, critical for the development and maturation of neutrophils...
March 13, 2018: Blood Advances
https://www.readbyqxmd.com/read/29459374/rescue-of-learning-and-memory-deficits-in-the-human-nonsyndromic-intellectual-disability-cereblon-knock-out-mouse-model-by-targeting-the-amp-activated-protein-kinase-mtorc1-translational-pathway
#8
Charlotte C Bavley, Richard C Rice, Delaney K Fischer, Amanda K Fakira, Maureen Byrne, Maria Kosovsky, Bryant K Rizzo, Dolores Del Prete, Armin Alaedini, Jose A Morón, Joseph J Higgins, Luciano D'Adamio, Anjali M Rajadhyaksha
A homozygous nonsense mutation in the cereblon ( CRBN ) gene results in autosomal recessive, nonsyndromic intellectual disability that is devoid of other phenotypic features, suggesting a critical role of CRBN in mediating learning and memory. In this study, we demonstrate that adult male Crbn knock-out ( Crbn KO ) mice exhibit deficits in hippocampal-dependent learning and memory tasks that are recapitulated by focal knock-out of Crbn in the adult dorsal hippocampus, with no changes in social or repetitive behavior...
March 14, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/29449372/ligand-mediated-protein-degradation-reveals-functional-conservation-among-sequence-variants-of-the-cul4-type-e3-ligase-substrate-receptor-cereblon
#9
Afua A Akuffo, Aileen Y Alontaga, Rainer Metcalf, Matthew S Beatty, Andreas Becker, Jessica M McDaniel, Rebecca S Hesterberg, William E Goodheart, Steven Gunawan, Muhammad Ayaz, Yan Yang, Md Rezaul Karim, Morgan E Orobello, Kenyon Daniel, Wayne Guida, Jeffrey A Yoder, Anjali M Rajadhyaksha, Ernst Schönbrunn, Harshani R Lawrence, Nicholas J Lawrence, Pearlie K Epling-Burnette
Upon binding to thalidomide and other immunomodulatory drugs, the E3 ligase substrate receptor cereblon (CRBN) promotes proteosomal destruction by engaging the DDB1-CUL4A-Roc1-RBX1 E3 ubiquitin ligase in human cells but not in mouse cells, suggesting that sequence variations in CRBN may cause its inactivation. Therapeutically, CRBN engagers have the potential for broad applications in cancer and immune therapy by specifically reducing protein expression through targeted ubiquitin-mediated degradation. To examine the effects of defined sequence changes on CRBN's activity, we performed a comprehensive study using complementary theoretical, biophysical, and biological assays aimed at understanding CRBN's nonprimate sequence variations...
April 20, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29410497/the-neuroprotective-effect-of-thalidomide-against-ischemia-through-the-cereblon-mediated-repression-of-ampk-activity
#10
Naoya Sawamura, Mariko Yamada, Miku Fujiwara, Haruka Yamada, Hideki Hayashi, Norio Takagi, Toru Asahi
Thalidomide was originally used as a sedative and found to be a teratogen, but now thalidomide and its derivatives are widely used to treat haematologic malignancies. Accumulated evidence suggests that thalidomide suppresses nerve cell death in neurologic model mice. However, detailed molecular mechanisms are unknown. Here we examined the molecular mechanism of thalidomide's neuroprotective effects, focusing on its target protein, cereblon (CRBN), and its binding protein, AMP-activated protein kinase (AMPK), which plays an important role in maintaining intracellular energy homeostasis in the brain...
February 6, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29370161/crl4-antagonizes-scffbxo7-mediated-turnover-of-cereblon-and-bk-channel-to-regulate-learning-and-memory
#11
Tianyu Song, Shenghui Liang, Jiye Liu, Tingyue Zhang, Yifei Yin, Chenlu Geng, Shaobing Gao, Yan Feng, Hao Xu, Dongqing Guo, Amanda Roberts, Yuchun Gu, Yong Cang
Intellectual disability (ID), one of the most common human developmental disorders, can be caused by genetic mutations in Cullin 4B (Cul4B) and cereblon (CRBN). CRBN is a substrate receptor for the Cul4A/B-DDB1 ubiquitin ligase (CRL4) and can target voltage- and calcium-activated BK channel for ER retention. Here we report that ID-associated CRL4CRBN mutations abolish the interaction of the BK channel with CRL4, and redirect the BK channel to the SCFFbxo7 ubiquitin ligase for proteasomal degradation. Glioma cell lines harbouring CRBN mutations record density-dependent decrease of BK currents, which can be restored by blocking Cullin ubiquitin ligase activity...
January 2018: PLoS Genetics
https://www.readbyqxmd.com/read/29358579/structural-basis-of-thalidomide-enantiomer-binding-to-cereblon
#12
Tomoyuki Mori, Takumi Ito, Shujie Liu, Hideki Ando, Satoshi Sakamoto, Yuki Yamaguchi, Etsuko Tokunaga, Norio Shibata, Hiroshi Handa, Toshio Hakoshima
Thalidomide possesses two optical isomers which have been reported to exhibit different pharmacological and toxicological activities. However, the precise mechanism by which the two isomers exert their different activities remains poorly understood. Here, we present structural and biochemical studies of (S)- and (R)-enantiomers bound to the primary target of thalidomide, cereblon (CRBN). Our biochemical studies employed deuterium-substituted thalidomides to suppress optical isomer conversion, and established that the (S)-enantiomer exhibited ~10-fold stronger binding to CRBN and inhibition of self-ubiquitylation compared to the (R)-enantiomer...
January 22, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29356495/translation-termination-factor-gspt1-is-a-phenotypically-relevant-off-target-of-heterobifunctional-phthalimide-degraders
#13
Mette Ishoey, Someth Chorn, Natesh Singh, Martin G Jaeger, Matthias Brand, Joshiawa Paulk, Sophie Bauer, Michael A Erb, Katja Parapatics, André C Müller, Keiryn L Bennett, Gerhard F Ecker, James E Bradner, Georg E Winter
Protein degradation is an emerging therapeutic strategy with a unique molecular pharmacology that enables the disruption of all functions associated with a target. This is particularly relevant for proteins depending on molecular scaffolding, such as transcription factors or receptor tyrosine kinases (RTKs). To address tractability of multiple RTKs for chemical degradation by the E3 ligase CUL4-RBX1-DDB1-CRBN (CRL4CRBN ), we synthesized a series of phthalimide degraders based on the promiscuous kinase inhibitors sunitinib and PHA665752...
March 16, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/29353038/cereblon-crbn-deletion-reverses-streptozotocin-induced-diabetic-osteoporosis-in-mice
#14
Cong Yao, Xiong Guo, Wan-Xia Yao, Chun Zhang
Diabetes mellitus is a major cause to induce osteoporosis. Though the pathogenesis of osteoporosis progression has been well investigated, its still not fully understood. Recently, cereblon (CRBN) was considered as a negative modulator of adenosine monophosphate-activated protein kinase (AMPK) in vitro and in vivo. Here, we presented results indicating that CRBN could effectively regulate osteoporosis development. In STZ-induced wild type (WT) mice with diabetes, the osteoclasts were highly increased along with the deterioration of bone structure...
February 12, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29348877/role-of-irf4-in-resistance-to-immunomodulatory-imid-compounds-%C3%A2-in-waldenstr%C3%A3-m-s-macroglobulinemia
#15
Elisabeth Bertrand, Nathalie Jouy, Salomon Manier, Guillemette Fouquet, Stéphanie Guidez, Eileen Boyle, Stéphanie Noel, Cécile Tomowiak, Charles Herbaux, Susanna Schraen, Claude Preudhomme, Bruno Quesnel, Stéphanie Poulain, Xavier Leleu
Background: Immunomodulatory drugs, IMid compounds, are active in Waldenström's macroglobulinemia (WM), although in a lesser extent than multiple myeloma, where it was initially developed. We hypothesized WM tumour cells might develop mechanisms of resistance, and sought to identify and describe these mechanisms. Material and Method: MM and WM-derived cell lines, and Waldenström's CD19+ cells were treated using both lenalidomide and pomalidomide. Stable CRBN expressing cells were generated...
December 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/29251720/pharmacological-perturbation-of-cdk9-using-selective-cdk9-inhibition-or-degradation
#16
Calla M Olson, Baishan Jiang, Michael A Erb, Yanke Liang, Zainab M Doctor, Zinan Zhang, Tinghu Zhang, Nicholas Kwiatkowski, Myriam Boukhali, Jennifer L Green, Wilhelm Haas, Tyzoon Nomanbhoy, Eric S Fischer, Richard A Young, James E Bradner, Georg E Winter, Nathanael S Gray
Cyclin-dependent kinase 9 (CDK9), an important regulator of transcriptional elongation, is a promising target for cancer therapy, particularly for cancers driven by transcriptional dysregulation. We characterized NVP-2, a selective ATP-competitive CDK9 inhibitor, and THAL-SNS-032, a selective CDK9 degrader consisting of a CDK-binding SNS-032 ligand linked to a thalidomide derivative that binds the E3 ubiquitin ligase Cereblon (CRBN). To our surprise, THAL-SNS-032 induced rapid degradation of CDK9 without affecting the levels of other SNS-032 targets...
February 2018: Nature Chemical Biology
https://www.readbyqxmd.com/read/29170136/cereblon-deficiency-confers-resistance-against-polymicrobial-sepsis-by-the-activation-of-amp-activated-protein-kinase-and-heme-oxygenase-1
#17
Minchan Gil, Yun Kyu Kim, Ha Yeong Kim, Hyo-Kyung Pak, Chan-Sik Park, Kyung Jin Lee
Cereblon (CRBN) has a pleiotropic role in important cellular processes and is a potential therapeutic target in several diseases, including mental retardation, cancer, and metabolic disorders. The role of CRBN in polymicrobial sepsis induced by cecal ligation and puncture (CLP) was investigated using CRBN-deficient (KO) mice. Survival following CLP was significantly higher in KO mice compared to wild-type (WT) controls (50% vs 0% at day 6 after CLP). The improved survival of KO mice was accompanied by reduced peripheral blood bacterial load and lung injury...
January 1, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29130642/dual-inhibition-of-dnmts-and-ezh2-can-overcome-both-intrinsic-and-acquired-resistance-of-myeloma-cells-to-imids-in-a-cereblon-independent-manner
#18
Konstantinos Dimopoulos, Alexandra Søgaard Helbo, Helga Fibiger Munch-Petersen, Lene Sjö, Jesper Christensen, Lasse Sommer Kristensen, Fazila Asmar, Niels Emil Ulrich Hermansen, Casey O'Connel, Peter Gimsing, Gangning Liang, Kirsten Grønbaek
Thalidomide and its derivatives, lenalidomide and pomalidomide (also known as IMiDs), have significantly changed the treatment landscape of multiple myeloma, and the recent discovery of cereblon (CRBN) as their direct biological target has led to a deeper understanding of their complex mechanism of action. In an effort to comprehend the precise mechanisms behind the development of IMiD resistance and examine whether it is potentially reversible, we established lenalidomide-resistant (-LR) and pomalidomide-resistant (-PR) human myeloma cell lines from two IMiD-sensitive cell lines, OPM2 and NCI-H929, by continuous culture in the presence of lenalidomide or pomalidomide for 4-6 months, until acquirement of stable resistance...
February 2018: Molecular Oncology
https://www.readbyqxmd.com/read/29129718/lessons-in-protac-design-from-selective-degradation-with-a-promiscuous-warhead
#19
Daniel P Bondeson, Blake E Smith, George M Burslem, Alexandru D Buhimschi, John Hines, Saul Jaime-Figueroa, Jing Wang, Brian D Hamman, Alexey Ishchenko, Craig M Crews
Inhibiting protein function selectively is a major goal of modern drug discovery. Here, we report a previously understudied benefit of small molecule proteolysis-targeting chimeras (PROTACs) that recruit E3 ubiquitin ligases to target proteins for their ubiquitination and subsequent proteasome-mediated degradation. Using promiscuous CRBN- and VHL-recruiting PROTACs that bind >50 kinases, we show that only a subset of bound targets is degraded. The basis of this selectivity relies on protein-protein interactions between the E3 ubiquitin ligase and the target protein, as illustrated by engaged proteins that are not degraded as a result of unstable ternary complexes with PROTAC-recruited E3 ligases...
January 18, 2018: Cell Chemical Biology
https://www.readbyqxmd.com/read/28978850/recent-topics-in-imids-and-cereblon
#20
Takumi Ito, Hiroshi Handa
Immunomodulatory drugs (IMiDs) are a new class of anticancer compounds that are derived from thalidomide. Lenalidomide and pomalidomide are well-known IMiDs, and they have already been approved by FDA for the treatment of several diseases, including multiple myeloma. Cereblon (CRBN) is a common primary target for IMiDs. It works as a substrate receptor of CRL4. Accumulating evidence has shown that the substrate specificity of CRL4CRBN is altered by ligands such as IMiDs. Recently, novel CRBN-binding compounds have been developed and are called "cereblon modulators"...
2017: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
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