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CRBN interactions - Protein interaction study using C-terminally tagged Cereblon

ABSTRACT: Protein interaction study using C-terminally tagged Cereblon

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Simone Lemeer

LAB HEAD: Bernhard Kuster

PROVIDER: PXD003440 | Pride | 2016-05-24

REPOSITORIES: Pride

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			Action	DRS
	00673_A01_P005065_B00A_A00_R1.raw	Raw
	00673_A02_P005065_B00I_A00_R1.raw	Raw
	00673_A03_P005066_B00E_A00_R1.raw	Raw
	00673_A04_P005067_B00A_A00_R1.raw	Raw
	00673_A05_P005067_B00I_A00_R1.raw	Raw

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Cereblon expression is required for the anti-myeloma activity of lenalidomide and pomalidomide

Project description:This SuperSeries is composed of the following subset Series: GSE31421: Cereblon expression is required for the anti-myeloma activity of lenalidomide and pomalidomide [expression profiling] GSE31451: Cereblon expression is required for the anti-myeloma activity of lenalidomide and pomalidomide [aCGH] Refer to individual Series

2011-09-30 | E-GEOD-31452 | biostudies-arrayexpress

Selective degradation-inducing probes for studying cereblon (CRBN) biology.

Project description:Targeted protein degradation represents a rapidly growing area in drug discovery and development. Moreover, small molecules that induce the targeted degradation of a given protein also represent an important addition to the chemical probes toolbox as these compounds can achieve selective protein knockdown, thus providing an approach that is orthogonal to genetic knockdowns. In order to develop degradation-inducing chemical probes for studying cereblon (CRBN) biology, we generated six CRBN-CRBN (homo-PROTAC) degraders and six CRBN-VHL (hetero-PROTAC) degraders. From these compounds we identified two potent and selective CRBN degraders (ZXH-4-130 and ZXH-4-137), both of which are CRBN-VHL compounds. We characterized these lead degraders by quantitative proteomics in five cell lines (MM1.S, Kelly, SK-N-DZ, HEK293T, and MOLT-4) and observed high selectivity for CRBN in all cell lines. Furthermore, we directly compared our compounds to current lead CRBN degraders and demonstrated how these probes can be used as chemical knockdown reagents for studying CRBN-dependent processes. Overall, our work provides a roadmap for thorough degrader characterization by combination western and proteomic analysis, as illustrated by the identification of ZXH-4-130 and ZXH-4-137 as CRBN-knockdown tool compounds suitable for cell-based studies.

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Project description:Thalidomide and other immunomodulatory drugs are effective therapies for certain hematological cancers where they kill tumor cells and stimulate T-cell immunity. These compounds mediate their functions by binding to and altering substrate specificity of cereblon (CRBN), an E3-ubiquitin ligase component of the DDB1/Cul4/Rbx1 complex3-5. Here, we report the results of crbn genetic deficiency in a mouse, which revealed CRBN functions as a suppressor of T-cell receptor (TCR) activation. We used microarrays to analyze the cereblon regulated gene expression changes following activation of wild type or cereblon knock out murine T-cells.

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Project description:Thalidomide has a dark history as a teratogen, but in recent years its derivates have been shown to function as a chemotherapeutic agent. These drugs bind cereblon (CRBN), the substrate receptor of an E3 ubiquitin ligase complex and modify its degradation targets. Despite these insights, remarkably little is known about the normal function of cereblon in development. Here we employ Ciona, an invertebrate chordate, to identify endogenous Crbn targets. In Ciona, Crbn is specifically expressed in developing muscles during tail elongation before they acquire contractile activity. Crbn expression is activated by Mrf, the ortholog of MYOD1, a transcription factor important for muscle differentiation. CRISPR/Cas9-mediated mutations of Crbn lead to precocious onset of muscle contractions. By contrast, overexpression of Crbn delays contractions and is associated with decreased expression of contractile protein genes such as troponin. This reduction is possibly due to reduced Mrf protein levels without altering Mrf mRNA levels. Our findings suggest that Myod and Crbn form a negative feedback loop to control the precision of muscle differentiation during tail elongation.

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De-Novo Design of Cereblon (CRBN) Effectors Guided by Natural Hydrolysis Products of Thalidomide Derivatives.

Project description:Targeted protein degradation via cereblon (CRBN), a substrate receptor of an E3 ubiquitin ligase complex, is an increasingly important strategy in various clinical settings, in which the substrate specificity of CRBN is altered via the binding of small-molecule effectors. To date, such effectors are derived from thalidomide and confer a broad substrate spectrum that is far from being fully characterized. Here, we employed a rational and modular approach to design novel and minimalistic CRBN effectors. In this approach, we took advantage of the binding modes of hydrolyzed metabolites of several thalidomide-derived effectors, which we elucidated via crystallography. These yielded key insights for the optimization of the minimal core binding moiety and its linkage to a chemical moiety that imparts substrate specificity. Based on this scaffold, we present a first active de-novo CRBN effector that is able to degrade the neo-substrate IKZF3 in the cell culture.

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Project description:We present a first-in-class GSPT1-selective CELMoD, CC-90009, which is currently in a phase 1 clinical trial for the treatment of relapsed or refractory (R/R) AML (CC-90009-AML-001; NCT02848001). Biochemical, structural and molecular characterization supports that CC-90009 coopts the CUL4-DDB1-CRBN-RBX1 (CRL4-CRBN) E3 ubiquitin ligase complex to selectively target GSPT1 for ubiquitination and proteasomal degradation, culminating in rapid induction of apoptosis and growth inhibition in AML cell lines and patient leukemic blasts. Knockout of ILF2/ILF3 decreased the production of full-length CRBN transcript via modulating CRBN mRNA alternative splicing, leading to significant downregulation of cereblon expression and hence diminished response to CC-90009.

2021-02-05 | GSE154257 | GEO

Mutations in CRBN and other cereblon pathway genes are infrequently associated with acquired resistance to immunomodulatory drugs.

Project description: Not available

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Cereblon influences the timing of muscle differentiation in Ciona tadpoles

Project description:Cereblon influences the timing of muscle differentiation in Ciona tadpoles

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Detection and quantification of C-terminally tagged proteins by in-gel fluorescence.

Project description:The analysis of recombinant proteins in complex solutions is often accomplished with tag-specific antibodies in western blots. Recently, I introduced an antibody-free alternative wherein tagged proteins are visualized directly within polyacrylamide gels. For this, I used the protein ligase Connectase to selectively attach fluorophores to target proteins possessing an N-terminal recognition sequence. In this study, I extend this methodology to encompass the detection and quantification of C-terminally tagged proteins. Similar to the N-terminal labeling method, this adapted procedure offers increased speed, heightened sensitivity, and an improved signal-to-noise ratio when compared to western blots. It also eliminates the need for sample-specific optimization, enables more consistent and precise quantifications, and uses freely available reagents. This study broadens the applicability of in-gel fluorescence detection methods and thereby facilitates research on recombinant proteins.

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A Cereblon Modulator CC-885 Induces CRBN- and p97-Dependent PLK1 Degradation and Synergizes with Volasertib to Suppress Lung Cancer.

Project description:Therapeutic targeting of advanced or metastatic non-small-cell lung cancer (NSCLC) represents a major goal of clinical treatment. Polo-like kinase 1 (PLK1) is an essential mitotic kinase in cell cycle progression and is associated with oncogenesis in a large spectrum of cancer types, including NSCLC. Volasertib (BI 6727) is a potent, selective, PLK1 inhibitor that is currently under phase 2 clinical trials with modest antitumor activity against solid tumors. As the combination of volasertib with pemetrexed does not improve efficacy for NSCLC treatment, it is crucial to identify compounds that could enhance efficacy with volasertib. Immunomodulatory drugs (IMiDs) bind to E3 ligase CRBN and repurposes it to ubiquitinate other proteins as neo-substrates, representing an effective treatment for hematologic malignancies. In this study, by screening IMiDs, we found that a novel CRBN modulator, CC-885, can synergistically inhibit NSCLC with volasertib both in vitro and in vivo. This synergistic effect overcomes volasertib resistance caused by PLK1 mutations and is compromised in CRBN-or p97-depleted cells. Mechanistically, CC-885 selectively promotes CRBN- and p97-dependent PLK1 ubiquitination and degradation, thereby enhancing the sensitivity of NSCLC to volasertib. In conclusion, our findings reveal that PLK1 is a neo-substrate of CUL4-CRBN induced by CC-885 and represent a combinational approach for treating NSCLC.

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