A novel effect of thalidomide and its analogs: suppression of cereblon ubiquitination enhances ubiquitin ligase function

Liu, Yaobin; Huang, Xiangao; He, Xian; Zhou, Yanqing; Jiang, Xiaogang; Chen‐Kiang, Selina; Jaffrey, Samie R.; Xu, Guoqiang

doi:10.1096/fj.15-274050

Cited by 46 publications

(48 citation statements)

References 35 publications

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“…Cereblon, the original target for the IMiDs, is a cullin-RING E3 ligase. By controlling which proteins are tagged and transferred to the proteasome, the function of the 26S proteasome is consequently inhibited [58,59]. E3 ligases fall into four classes: (i) Really Interesting New Gene (RINGs) (which target proteins and mediate the transfer of ubiquitin from an E2), (ii) E6-AP Carboxyl-Terminus (HECTs (which are homologous to E6 and transfer ubiquitin to their own cysteine residues and then to a substrate), (iii) the U-boxes (which behave like RINGs), and (iv) the RING-Inbetween-RINGs (which behave like hybrids of RINGs and HECTs).…”

Section: Proteasome Inhibitors In Clinical Studiesmentioning

confidence: 99%

Targeting the ubiquitin-proteasome system for cancer treatment: discovering novel inhibitors from nature and drug repurposing

Soave

Guerin

Liu

et al. 2017

Cancer Metastasis Rev

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In the past fifteen years, the proteasome has been validated as an anticancer drug target and 20S proteasome inhibitors (such as bortezomib and carfilzomib) have been approved by the FDA for the treatment of multiple myeloma and some other liquid tumors. However, there are shortcomings of clinical proteasome inhibitors, including severe toxicity, drug resistance and no effect in solid tumors. At the same time, extensive research has been conducted in the areas of natural compounds and old drug repositioning toward the goal of discovering effective, economical, low toxicity proteasome-inhibitory anticancer drugs. A variety of dietary polyphenols, medicinal molecules, metallic complexes and metal-binding compounds have been found to be able to selectively inhibit tumor cellular proteasomes and induce apoptotic cell death in vitro and in vivo, supporting the clinical success of specific 20S proteasome inhibitors bortezomib and carfilzomib. Therefore, the discovery of natural proteasome inhibitors and researching old drugs with proteasome inhibitory properties may provide an alternative strategy for improving the current status of cancer treatment and even prevention.

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Section: Proteasome Inhibitors In Clinical Studiesmentioning

confidence: 99%

Targeting the ubiquitin-proteasome system for cancer treatment: discovering novel inhibitors from nature and drug repurposing

Soave

Guerin

Liu

et al. 2017

Cancer Metastasis Rev

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“…Interestingly, lenalidomide treatment modestly increased CRBN protein expression (Figure 6B–C), consistent with recent reports that lenalidomide stabilizes CRBN. (23)…”

Section: Resultsmentioning

confidence: 99%

Lenalidomide Stabilizes the Erythropoietin Receptor by Inhibiting the E3 Ubiquitin Ligase RNF41

et al. 2016

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In a subset of patients with non-del(5q) myelodysplastic syndrome (MDS), lenalidomide promotes erythroid lineage competence and effective erythropoiesis. To determine the mechanism by which lenalidomide promotes erythropoiesis, we investigated its action on erythropoietin receptor (EpoR) cellular dynamics. Lenalidomide upregulated expression and stability of JAK2-associated EpoR in UT7 erythroid cells and primary CD71+ erythroid progenitors. The effects of lenalidomide on receptor turnover were Type I cytokine receptor specific, as evidenced by co-regulation of the IL-3β receptor but not c-Kit. To elucidate this mechanism, we investigated the effects of lenalidomide on the E3 ubiquitin ligase RNF41. Lenalidomide promoted EpoR/RNF41 association and inhibited RNF41 auto-ubiquitination, accompanied by a reduction in EpoR ubiquitination. To confirm that RNF41 is the principal target responsible for EpoR stabilization, HEK293T cells were transfected with EpoR and/or RNF41 gene expression vectors. Steady state EpoR expression was reduced in EpoR/RNF41 cells while EpoR upregulation by lenalidomide was abrogated, indicating that cellular RNF41 is a critical determinant of drug-induced receptor modulation. Notably, shRNA suppression of CRBN gene expression failed to alter EpoR upregulation, indicating that drug-induced receptor modulation is independent of cereblon. Immunohistochemical staining showed that RNF41 expression decreased in primary erythroid cells of lenalidomide responding patients, suggesting that cellular RNF41 expression merits investigation as a biomarker for lenalidomide response. Our findings indicate that lenalidomide has E3 ubiquitin ligase inhibitory effects that extend to RNF41, and that inhibition of RNF41 auto-ubiquitination promotes membrane accumulation of signaling competent JAK2/EpoR complexes that augment Epo responsiveness.

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“…As we described in Abstract and Introduction, CRBN, like DDB1, is a component of the cullin 4 ring E3 ubiquitin ligase complex (CRL4). Auto-ubiquitination of CRBN was inhibited by thalidomide in vitro, suggesting that thalidomide is an inhibitor of E3 ubiquitin ligase [77].…”

Section: Cereblon As the Direct Target Protein Of Imidsmentioning

confidence: 97%

Immunomodulatory drugs and their therapeutic effect in hematological malignancies through cereblon

Fuchs¹

2017

Hematol Med Oncol

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Immunomodulatory drugs (IMiDs), today also known as cereblon (CRBN) binding drugs, are therapeutically important anti-cancer and anti-inflammatory drugs. IMiDs are analogs of their prototype compound thalidomide. IMiDs have immune-modulation, anti-angiogenic, anti-inflammatory and anti-proliferative effects. CRBN is a component and substrate receptor of the Cullin 4 Ring E3 Ubiquitin Protein Ligase complex (CRL4). CRL4 consists of Cullin 4, RING finger protein (Roc1), and DNA damage binding protein 1 (DDB1). CRBN binds to its substrate proteins and it leads to ubiquitination of these substrates by the CRL4. CRBN is also involved in IMiDs-mediated T-cell co-stimulation and cytokine production. CRBN is a primary target of thalidomide teratogenicity. The binding of IMiDs to CRBN is associated with cytotoxicity of IMiDs and is used to treat multiple myeloma (MM), myelodysplastic syndromes (MDS), lymphomas and chronic lymphocytic leukemia. CRBN is composed of an N-terminal ATP-dependent serine protease Lon-like domain, which links to the E3 ubiquitin protein ligase complex CRL4, and a C-terminal domain, which binds IMiDs. CRBN binding is mediated by a glutarimide ring in thalidomide, lenalidomide, pomalidomide, CC-122, CC-220, CC-885 and CC-90009. Development of effector molecules mediating targeted ubiquitination of disease related proteins through cereblon is a new important way in pharmacology.

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A novel effect of thalidomide and its analogs: suppression of cereblon ubiquitination enhances ubiquitin ligase function

Cited by 46 publications

References 35 publications

Targeting the ubiquitin-proteasome system for cancer treatment: discovering novel inhibitors from nature and drug repurposing

Targeting the ubiquitin-proteasome system for cancer treatment: discovering novel inhibitors from nature and drug repurposing

Lenalidomide Stabilizes the Erythropoietin Receptor by Inhibiting the E3 Ubiquitin Ligase RNF41

Immunomodulatory drugs and their therapeutic effect in hematological malignancies through cereblon

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