Functional modulation of AMP-activated protein kinase by cereblon

Lee, Kwang Min; Jo, Sooyeon; Kim, Sujeong; Lee, Jongwon; Park, Chul–Seung

doi:10.1016/j.bbamcr.2011.01.005

Cited by 79 publications

(101 citation statements)

References 44 publications

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“…8). These findings not only strengthen the idea that CRBN is an endogenous negative regulator of AMPK (4,5), but also provide a testable hypothesis regarding the mechanism by which the nonsense mutation in CRBN causes mental deficit in humans (Fig. 9).…”

Section: Discussionsupporting

confidence: 59%

“…Furthermore, in whole-body Crbn-deficient mice, we also observed severe deficits in behaviors involving hippocampal function, but no noticeable abnormalities in motor function. 4 Despite its potential involvement in higher brain function, however, the cellular roles of CRBN in the central nervous system are still controversial, and the functional consequences of the C-terminal deletion found in mutant CRBN have never been characterized.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, CRBN is the primary target of thalidomide-induced teratogenicity, and is thought to function as a substrate receptor of an E3 ubiquitin ligase complex (3). A recent study showed that CRBN interacts with the ␣ subunit of adenosine monophosphate-activated protein kinase (AMPK) and inhibits the activation of AMPK in vitro as well as in vivo (4,5).…”

mentioning

confidence: 99%

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Functional Effects of a Pathogenic Mutation in Cereblon (CRBN) on the Regulation of Protein Synthesis via the AMPK-mTOR Cascade

Lee

Yang

Choi

et al. 2014

Journal of Biological Chemistry

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Background: Deficiency or nonsense mutation of CRBN causes memory deficits. Results: Truncated CRBN has insufficient affinity for AMPK␣ and cannot modulate the AMPK-mTOR pathway. Conclusion: CRBN modulates protein synthesis through the AMPK-mTOR pathway, and may be critical for certain forms of memory encoding. Significance: Our findings suggest the first plausible mechanism for the phenotype resulting from the CRBN mutation.

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Section: Discussionsupporting

confidence: 59%

Section: Discussionmentioning

confidence: 99%

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Functional Effects of a Pathogenic Mutation in Cereblon (CRBN) on the Regulation of Protein Synthesis via the AMPK-mTOR Cascade

Lee

Yang

Choi

et al. 2014

Journal of Biological Chemistry

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“…PEXs are associated with energy metabolism. Interestingly, CRBN has been reported to associate with and negatively regulate AMP-activated protein kinase, 29 which play a role in cellular energy homeostasis.…”

Section: Discussionmentioning

confidence: 99%

RNA interference screening identifies lenalidomide sensitizers in multiple myeloma, including RSK2

Zhu

Yin

Bruins

et al. 2015

Blood

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• High-throughput RNAi screening identified lenalidomide sensitizer genes, including RSK2, RAB, peroxisome, and potassium channel family members.• Knockdown or inhibition of RSK2 synergized with lenalidomide to induce myeloma cytotoxicity and downregulation of interferon regulatory factor 4 and MYC.To identify molecular targets that modify sensitivity to lenalidomide, we measured proliferation in multiple myeloma (MM) cells transfected with 27 968 small interfering RNAs in the presence of increasing concentrations of drug and identified 63 genes that enhance activity of lenalidomide upon silencing. Ribosomal protein S6 kinase (RPS6KA3 or RSK2) was the most potent sensitizer. Other notable gene targets included 5 RAB family members, 3 potassium channel proteins, and 2 peroxisome family members. Single genes of interest included I-k-B kinase-a (CHUK), and a phosphorylation dependent transcription factor (CREB1), which associate with RSK2 to regulate several signaling pathways. RSK2 knockdown induced cytotoxicity across a panel of MM cell lines and consistently increased sensitivity to lenalidomide. Accordingly, 3 small molecular inhibitors of RSK2 demonstrated synergy with lenalidomide cytotoxicity in MM cells even in the presence of stromal contact. Both RSK2 knockdown and small molecule inhibition downregulate interferon regulatory factor 4 and MYC, and provides an explanation for the synergy between lenalidomide and RSK2 inhibition. Interestingly, RSK2 inhibition also sensitized MM cells to bortezomib, melphalan, and dexamethasone, but did not downregulate Ikaros or influence lenalidomide-mediated downregulation of tumor necrosis factor-a or increase lenalidomide-induced IL-2 upregulation. In summary, inhibition of RSK2 may prove a broadly useful adjunct to MM therapy. (Blood. 2015;125(3): [483][484][485][486][487][488][489][490][491] IntroductionThe immunomodulatory drugs (IMiDs) thalidomide, lenalidomide, and pomalidomide are broadly used in the treatment of patients with multiple myeloma (MM) and have produced significant clinical advances in both newly diagnosed and advanced disease.1,2 However, only 30% of relapsed MM patients respond to single agent IMiD therapy and most patients eventually develop drug resistance. The underlying mechanisms defining this nonresponsiveness are largely unknown. Recently, Cereblon (CRBN) and Ikaros/Aiolos (IZKF1 and IZKF3) were identified as the molecular targets of IMiDs in MM 3-6 via their ability to induce cytotoxicity by inhibiting interferon regulatory factor 4 (IRF4) and MYC. The action of IMiDs appears to be mediated via binding to CRBN with activation of its associated E3 ubiquitin ligase and subsequent proteasomal degradation of Ikaros. 5,6 Furthermore, low CRBN and IZKF1 levels are associated with IMiD resistance, 3,4,7,8 but other parallel pathways or downstream events that enhance or preclude drug responsiveness are unknown.In the present study, a druggable genome short interfering RNA (siRNA) screen was used to identify 63 genes whose loss of expression enhance...

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“…It has been reported that CRBN can directly interact with several proteins, such as AMP-activated protein kinase (10), the large conductance calcium-activated potassium channel (11), voltage-gated chloride channels (12), and the 20 S core proteasome subunit ␤ type 4 (13). None of these proteins has yet been shown to be targeted by CRL4 as a result of their binding to CRBN.…”

mentioning

confidence: 99%

A Mental Retardation-linked Nonsense Mutation in Cereblon Is Rescued by Proteasome Inhibition

Jiang

Jaffrey

2013

Journal of Biological Chemistry

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Background: A nonsense mutation in cereblon, which results in the loss of the last 24 amino acids in the protein, causes mental retardation. Results: This mutant form of cereblon undergoes autoubiquitination by a CRL4 E3 ligase complex, leading to enhanced proteasomal degradation. Conclusion:The protein level of the mutant cereblon can be rescued by proteasome inhibition. Significance: These findings provide an approach for the treatment of mental retardation associated with this cereblon mutation.

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Functional modulation of AMP-activated protein kinase by cereblon

Cited by 79 publications

References 44 publications

Functional Effects of a Pathogenic Mutation in Cereblon (CRBN) on the Regulation of Protein Synthesis via the AMPK-mTOR Cascade

Functional Effects of a Pathogenic Mutation in Cereblon (CRBN) on the Regulation of Protein Synthesis via the AMPK-mTOR Cascade

RNA interference screening identifies lenalidomide sensitizers in multiple myeloma, including RSK2

A Mental Retardation-linked Nonsense Mutation in Cereblon Is Rescued by Proteasome Inhibition

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