Read by QxMD icon Read


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 knockout (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...
March 12, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
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
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, non-syndromic intellectual disability (ARNSID) 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 knockout ( Crbn KO ) mice exhibit deficits in hippocampal-dependent learning and memory tasks that are recapitulated by focal knockout of Crbn in the adult dorsal hippocampus, with no changes in social or repetitive behavior...
February 19, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
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 Schonbrunn, 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 proteasomal 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 CRBNs activity, we performed a comprehensive study using complementary theoretical, biophysical, and biological assays aimed at understanding CRBNs non-primate sequence variations...
February 15, 2018: Journal of Biological Chemistry
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
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 25, 2018: PLoS Genetics
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
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...
January 22, 2018: ACS Chemical Biology
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...
January 15, 2018: Biochemical and Biophysical Research Communications
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
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...
December 18, 2017: Nature Chemical Biology
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
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...
November 11, 2017: Molecular Oncology
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...
November 9, 2017: Cell Chemical Biology
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 CRL4(CRBN) 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
Honorine Lebraud, Tom D Heightman
In a time of unprecedented challenges in developing potent, selective and well-tolerated protein inhibitors as therapeutics, drug hunters are increasingly seeking alternative modalities to modulate pharmacological targets. Selective inhibitors are achievable for only a fraction of the proteome, and are not guaranteed to elicit the desired response in patients, especially when pursuing targets identified through genetic knockdown. Targeted protein degradation holds the potential to expand the range of proteins that can be effectively modulated...
October 2, 2017: Essays in Biochemistry
Yuan Jian, Wen Gao, Chuanying Geng, Huixing Zhou, Yun Leng, Yanchen Li, Wenming Chen
The mechanism of the anti-myeloma effect of the immunomodulatory drug lenalidomide relies upon the binding of lenalidomide or an analogue to cereblon (CRBN) ubiquitin ligase, which inhibits it and results in the degradation of Ikaros-family zinc finger proteins 1 and 3 (IKZF1 and IKZF3). To determine whether the traditional Chinese medicine arsenic trioxide, could potentiate sensitivity of multiple myeloma (MM) cells to lenalidomide and identify the mechanism by which this happens, the present study investigated how arsenic trioxide affected CRBN on MM cell lines and examined the anti-myeloma effect and mechanism in the combination of arsenic trioxide and lenalidomide...
September 2017: Oncology Letters
Shuji Aida, Masashi Hozumi, Daiju Ichikawa, Kazuki Iida, Yuko Yonemura, Noriko Tabata, Taketo Yamada, Maiko Matsushita, Takeshi Sugai, Hiroshi Yanagawa, Yutaka Hattori
Despite the development of new drugs for multiple myeloma (MM), the prognosis of MM patients with high-risk cytogenetic abnormalities such as t (4; 14) and del17p remains poor. We reported that a novel phenylphthalimide derivative, TC11, induced apoptosis of MM cells in vitro and in vivo, and TC11 directly bound to α-tubulin and nucleophosmin-1 (NPM1). However, TC11 showed low water solubility and poor pharmacokinetic properties. Here we synthesized a water-soluble TC11-derivative, PEG(E)-TC11, in which HOEtO-TC11 is pegylated with PEG through an ester bond, and we examined its anti-myeloma activity...
November 4, 2017: Biochemical and Biophysical Research Communications
Barbara Kiesewetter, Ingrid Simonitsch-Klupp, Christoph Kornauth, Werner Dolak, Julius Lukas, Marius E Mayerhoefer, Markus Raderer
Lenalidomide is an active agent for the treatment of MALT lymphoma. Recently, high expression levels of cereblon (CRBN) and MUM1 have been associated with better response rates in multiple myeloma treated with lenalidomide. However, there are no data on CRBN and MUM1 expression in MALT lymphoma. In the current study, we have systematically investigated a potential correlation of CRBN/MUM1 immunohistochemical expression and response to lenalidomide-based therapy in a series of 46 patients with MALT lymphoma treated at the Medical University Vienna 2009 to 2014...
August 22, 2017: Hematological Oncology
Caroline M Robb, Jacob I Contreras, Smit Kour, Margaret A Taylor, Mohammad Abid, Yogesh A Sonawane, Muhammad Zahid, Daryl J Murry, Amarnath Natarajan, Sandeep Rana
Cyclin-dependent kinase 9 (CDK9), a member of the cyclin-dependent protein kinase (CDK) family, is involved in transcriptional elongation of several target genes. CDK9 is ubiquitously expressed and has been shown to contribute to a variety of malignancies such as pancreatic, prostate and breast cancers. Here we report the development of a heterobifunctional small molecule proteolysis targeting chimera (PROTAC) capable of cereblon (CRBN) mediated proteasomal degradation of CDK9. In HCT116 cells, it selectively degrades CDK9 while sparing other CDK family members...
July 4, 2017: Chemical Communications: Chem Comm
Fetch more papers »
Fetching more papers... Fetching...
Read by QxMD. Sign in or create an account to discover new knowledge that matter to you.
Remove bar
Read by QxMD icon Read

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"