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Cereblon in health and disease

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Abstract

Cereblon (CRBN) is a substrate receptor of the E3 ubiquitin ligase complex that has been linked to autosomal recessive non-syndromic mental retardation. Several key findings suggest diverse roles of CRBN, including its regulation of the large-conductance calcium- and voltage-activated potassium (BKCa) channels, regulation of thalidomide-binding proteins, and mediation of lenalidomide treatment in multiple myeloma. Recent studies also indicate that CRBN is involved in energy metabolism and negatively regulates AMP-activated protein kinase signaling. Mice with genetic depletion of CRBN are resistant to various stress conditions including a high-fat diet, endoplasmic reticulum stress, ischemia/reperfusion injury, and alcohol-related liver damage. In this review, we discuss the various roles of CRBN in human health and disease and suggest avenues for further research to enhance our basic knowledge and clinical application of CRBN.

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References

  1. Apaja PM, Foo B, Okiyoneda T, Valinsky WC, Barriere H, Atanasiu R, Ficker E, Lukacs GL, Shrier A (2013) Ubiquitination-dependent quality control of hERG K+ channel with acquired and inherited conformational defect at the plasma membrane. Mol Biol Cell 24:3787–3804. doi:10.1091/mbc.E13-07-0417

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Awan FT, Johnson AJ, Lapalombella R, Hu W, Lucas M, Fischer B, Byrd JC (2010) Thalidomide and lenalidomide as new therapeutics for the treatment of chronic lymphocytic leukemia. Leuk Lymphoma 51:27–38. doi:10.3109/10428190903350405

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Beauloye C, Bertrand L, Horman S, Hue L (2011) AMPK activation, a preventive therapeutic target in the transition from cardiac injury to heart failure. Cardiovasc Res 90:224–233. doi:10.1093/cvr/cvr034

    Article  CAS  PubMed  Google Scholar 

  4. Bjorklund CC, Lu L, Kang J, Hagner PR, Havens CG, Amatangelo M, Wang M, Ren Y, Couto S, Breider M, Ning Y, Gandhi AK, Daniel TO, Chopra R, Klippel A, Thakurta AG (2015) Rate of CRL4(CRBN) substrate Ikaros and Aiolos degradation underlies differential activity of lenalidomide and pomalidomide in multiple myeloma cells by regulation of c-Myc and IRF4. Blood Cancer J 5, e354. doi:10.1038/bcj.2015.66

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Blanz J, Schweizer M, Auberson M, Maier H, Muenscher A, Hubner CA, Jentsch TJ (2007) Leukoencephalopathy upon disruption of the chloride channel ClC-2. J Neurosci 27:6581–6589. doi:10.1523/JNEUROSCI.0338-07.2007

    Article  CAS  PubMed  Google Scholar 

  6. Broyl A, Kuiper R, van Duin M, van der Holt B, el Jarari L, Bertsch U, Zweegman S, Buijs A, Hose D, Lokhorst HM, Goldschmidt H, Sonneveld P (2013) High cereblon expression is associated with better survival in patients with newly diagnosed multiple myeloma treated with thalidomide maintenance. Blood 121:624–627. doi:10.1182/blood-2012-06-438101

    Article  CAS  PubMed  Google Scholar 

  7. Capdevila J, Tsukui T, Rodriquez Esteban C, Zappavigna V, Izpisua Belmonte JC (1999) Control of vertebrate limb outgrowth by the proximal factor Meis2 and distal antagonism of BMPs by Gremlin. Mol Cell 4:839–849. doi:10.1182/blood-2012-06-438101

    Article  CAS  PubMed  Google Scholar 

  8. Carter CJ (1981) Glutamine, glutamine synthetase and Huntington’s disease. Lancet 1:1427–1428. doi:10.1016/s0140-6736(81)92611-8

    Article  CAS  PubMed  Google Scholar 

  9. Cavo M (2011) A third-generation IMiD for MM. Blood 118:2931–2932. doi:10.1182/blood-2011-07-364315

    Article  CAS  PubMed  Google Scholar 

  10. Chang XB, Stewart AK (2011) What is the functional role of the thalidomide binding protein cereblon? Int J Biochem Mol Biol 2:287–294

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Chen YA, Peng YJ, Hu MC, Huang JJ, Chien YC, Wu JT, Chen TY, Tang CY (2015) The cullin 4A/B-DDB1-cereblon E3 ubiquitin ligase complex mediates the degradation of CLC-1 chloride channels. Sci Rep 5:10667. doi:10.1038/srep10667

    Article  PubMed  PubMed Central  Google Scholar 

  12. Contreras AV, Torres N, Tovar AR (2013) PPAR-alpha as a key nutritional and environmental sensor for metabolic adaptation. Adv Nutr 4:439–452. doi:10.3945/an.113.003798

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Damaj G, Lefrere F, Delarue R, Varet B, Furman R, Hermine O (2003) Thalidomide therapy induces response in relapsed mantle cell lymphoma. Leukemia 17:1914–1915. doi:10.1038/sj.leu.2403058

    Article  CAS  PubMed  Google Scholar 

  14. D’Amato RJ, Loughnan MS, Flynn E, Folkman J (1994) Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci U S A 91:4082–4085. doi:10.1073/pnas.91.9.4082

    Article  PubMed  PubMed Central  Google Scholar 

  15. Diaz-Rodriguez E, Pandiella A (2016) Modulation of cereblon levels by anti-myeloma agents. Leuk Lymphoma 57:167–176. doi:10.3109/10428194.2015.1037752

    Article  CAS  PubMed  Google Scholar 

  16. Dijkhuizen T, van Essen T, van der Vlies P, Verheij JB, Sikkema-Raddatz B, van der Veen AY, Gerssen-Schoorl KB, Buys CH, Kok K (2006) FISH and array-CGH analysis of a complex chromosome 3 aberration suggests that loss of CNTN4 and CRBN contributes to mental retardation in 3pter deletions. Am J Med Genet A 140:2482–2487. doi:10.1002/ajmg.a.31487

    Article  PubMed  Google Scholar 

  17. Dong Y, Zhang M, Liang B, Xie Z, Zhao Z, Asfa S, Choi HC, Zou MH (2010) Reduction of AMP-activated protein kinase alpha2 increases endoplasmic reticulum stress and atherosclerosis in vivo. Circulation 121:792–803. doi:10.1161/CIRCULATIONAHA.109.900928

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Fecteau JF, Corral LG, Ghia EM, Gaidarova S, Futalan D, Bharati IS, Cathers B, Schwaederle M, Cui B, Lopez-Girona A, Messmer D, Kipps TJ (2014) Lenalidomide inhibits the proliferation of CLL cells via a cereblon/p21(WAF1/Cip1)-dependent mechanism independent of functional p53. Blood 124:1637–1644. doi:10.1182/blood-2014-03-559591

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Fischer ES, Bohm K, Lydeard JR, Yang H, Stadler MB, Cavadini S, Nagel J, Serluca F, Acker V, Lingaraju GM, Tichkule RB, Schebesta M, Forrester WC, Schirle M, Hassiepen U, Ottl J, Hild M, Beckwith RE, Harper JW, Jenkins JL, Thoma NH (2014) Structure of the DDB1-CRBN E3 ubiquitin ligase in complex with thalidomide. Nature 512:49–53. doi:10.1038/nature13527

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Gandhi AK, Mendy D, Waldman M, Chen G, Rychak E, Miller K, Gaidarova S, Ren Y, Wang M, Breider M, Carmel G, Mahmoudi A, Jackson P, Abbasian M, Cathers BE, Schafer PH, Daniel TO, Lopez-Girona A, Thakurta A, Chopra R (2014) Measuring cereblon as a biomarker of response or resistance to lenalidomide and pomalidomide requires use of standardized reagents and understanding of gene complexity. Br J Haematol 164:233–244. doi:10.1111/bjh.12622

    Article  CAS  PubMed  Google Scholar 

  21. Giannopoulos K, Mertens D, Stilgenbauer S (2011) Treating chronic lymphocytic leukemia with thalidomide and lenalidomide. Expert Opin Pharmacother 12:2857–2864. doi:10.1517/14656566.2011.635644

    Article  CAS  PubMed  Google Scholar 

  22. Heintel D, Rocci A, Ludwig H, Bolomsky A, Caltagirone S, Schreder M, Pfeifer S, Gisslinger H, Zojer N, Jager U, Palumbo A (2013) High expression of cereblon (CRBN) is associated with improved clinical response in patients with multiple myeloma treated with lenalidomide and dexamethasone. Br J Haematol 161:695–700. doi:10.1111/bjh.12338

    Article  CAS  PubMed  Google Scholar 

  23. Hensley CT, Wasti AT, DeBerardinis RJ (2013) Glutamine and cancer: cell biology, physiology, and clinical opportunities. J Clin Invest 123:3678–3684. doi:10.1172/JCI69600

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Higgins JJ, Hao J, Kosofsky BE, Rajadhyaksha AM (2008) Dysregulation of large-conductance Ca2+-activated K+ channel expression in nonsyndromal mental retardation due to a cereblon p.R419X mutation. Neurogenetics 9:219–223. doi:10.1007/s10048-008-0128-2

    Article  CAS  PubMed  Google Scholar 

  25. Higgins JJ, Pucilowska J, Lombardi RQ, Rooney JP (2004) A mutation in a novel ATP-dependent Lon protease gene in a kindred with mild mental retardation. Neurology 63:1927–1931. doi:10.1212/01.wnl.0000146196.01316.a2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Higgins JJ, Tal AL, Sun X, Hauck SC, Hao J, Kosofosky BE, Rajadhyaksha AM (2010) Temporal and spatial mouse brain expression of cereblon, an ionic channel regulator involved in human intelligence. J Neurogenet 24:18–26. doi:10.3109/01677060903567849

    Article  CAS  PubMed  Google Scholar 

  27. Hohberger B, Enz R (2009) Cereblon is expressed in the retina and binds to voltage-gated chloride channels. FEBS Lett 583:633–637. doi:10.1016/j.febslet.2009.01.018

    Article  CAS  PubMed  Google Scholar 

  28. Huang SY, Lin CW, Lin HH, Yao M, Tang JL, Wu SJ, Chen YC, Lu HY, Hou HA, Chen CY, Chou WC, Tsay W, Chou SJ, Tien HF (2014) Expression of cereblon protein assessed by immunohistochemicalstaining in myeloma cells is associated with superior response of thalidomide- and lenalidomide-based treatment, but not bortezomib-based treatment, in patients with multiple myeloma. Ann Hematol 93:1371–1380. doi:10.1007/s00277-014-2063-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ito T, Ando H, Suzuki T, Ogura T, Hotta K, Imamura Y, Yamaguchi Y, Handa H (2010) Identification of a primary target of thalidomide teratogenicity. Science 327:1345–1350. doi:10.1126/science.1177319

    Article  CAS  PubMed  Google Scholar 

  30. Jamroziak K, Szemraj J, Robak T, Tukiendorf A, Giannopoulos K (2015) Cereblon expression predicts clinical response in chronic lymphocytic leukemia treated with a thalidomide/fludarabine regimen. Leuk Lymphoma 56:808–810. doi:10.3109/10428194.2014.933215

    Article  PubMed  Google Scholar 

  31. Jo S, Lee KH, Song S, Jung YK, Park CS (2005) Identification and functional characterization of cereblon as a binding protein for large-conductance calcium-activated potassium channel in rat brain. J Neurochem 94:1212–1224. doi:10.1111/j.1471-4159.2005.03344.x

    Article  CAS  PubMed  Google Scholar 

  32. Jonasova A, Bokorova R, Polak J, Vostry M, Kostecka A, Hajkova H, Neuwirtova R, Siskova M, Sponerova D, Cermak J, Mikulenkova D, Cervinek L, Brezinova J, Michalova K, Fuchs O (2015) High level of full-length cereblon mRNA in lower risk myelodysplastic syndrome with isolated 5q deletion is implicated in the efficacy of lenalidomide. Eur J Haematol 95:27–34. doi:10.1111/ejh.12457

    Article  CAS  PubMed  Google Scholar 

  33. Kim YD, Lee KM, Hwang SL, Chang HW, Kim KJ, Harris RA, Choi HS, Choi WS, Lee SE, Park CS (2015) Inhibition of cereblon by fenofibrate ameliorates alcoholic liver disease by enhancing AMPK. Biochim Biophys Acta 1852:2662–2670. doi:10.1016/j.bbadis.2015.09.014

    Article  CAS  PubMed  Google Scholar 

  34. Kim J, Lee KM, Park CS, Park WJ (2014) Ablation of cereblon attenuates myocardial ischemia-reperfusion injury. Biochem Biophys Res Commun 447:649–654. doi:10.1016/j.bbrc.2014.04.061

    Article  CAS  PubMed  Google Scholar 

  35. Kleefuss-Lie A, Friedl W, Cichon S, Haug K, Warnstedt M, Alekov A, Sander T, Ramirez A, Poser B, Maljevic S, Hebeisen S, Kubisch C, Rebstock J, Horvath S, Hallmann K, Dullinger JS, Rau B, Haverkamp F, Beyenburg S, Schulz H, Janz D, Giese B, Muller-Newen G, Propping P, Elger CE, Fahlke C, Lerche H (2009) CLCN2 variants in idiopathic generalized epilepsy. Nat Genet 41:954–955. doi:10.1038/ng0909-954

    Article  CAS  PubMed  Google Scholar 

  36. Kronke J, Fink EC, Hollenbach PW, MacBeth KJ, Hurst SN, Udeshi ND, Chamberlain PP, Mani DR, Man HW, Gandhi AK, Svinkina T, Schneider RK, McConkey M, Jaras M, Griffiths E, Wetzler M, Bullinger L, Cathers BE, Carr SA, Chopra R, Ebert BL (2015) Lenalidomide induces ubiquitination and degradation of CK1alpha in del(5q) MDS. Nature 523:183–188. doi:10.1038/nature14610

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Kronke J, Udeshi ND, Narla A, Grauman P, Hurst SN, McConkey M, Svinkina T, Heckl D, Comer E, Li X, Ciarlo C, Hartman E, Munshi N, Schenone M, Schreiber SL, Carr SA, Ebert BL (2014) Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science 343:301–305. doi:10.1126/science.1244851

    Article  PubMed  Google Scholar 

  38. Kudo N, Barr AJ, Barr RL, Desai S, Lopaschuk GD (1995) High rates of fatty acid oxidation during reperfusion of ischemic hearts are associated with a decrease in malonyl-CoA levels due to an increase in 5′-AMP-activated protein kinase inhibition of acetyl-CoA carboxylase. J Biol Chem 270:17513–17520. doi:10.1074/jbc.270.29.17513

    Article  CAS  PubMed  Google Scholar 

  39. Laumonnier F, Roger S, Guerin P, Molinari F, M’Rad R, Cahard D, Belhadj A, Halayem M, Persico AM, Elia M, Romano V, Holbert S, Andres C, Chaabouni H, Colleaux L, Constant J, Le Guennec JY, Briault S (2006) Association of a functional deficit of the BKCa channel, a synaptic regulator of neuronal excitability, with autism and mental retardation. Am J Psychiatry 163:1622–1629. doi:10.1176/ajp.2006.163.9.1622

    Article  PubMed  Google Scholar 

  40. Leclerc GM, Leclerc GJ, Kuznetsov JN, DeSalvo J, Barredo JC (2013) Metformin induces apoptosis through AMPK-dependent inhibition of UPR signaling in ALL lymphoblasts. PLoS ONE 8, e74420. doi:10.1371/journal.pone.0074420

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Lee KM, Jo S, Kim H, Lee J, Park CS (2011) Functional modulation of AMP-activated protein kinase by cereblon. Biochim Biophys Acta 1813:448–455. doi:10.1016/j.bbamcr.2011.01.005

    Article  CAS  PubMed  Google Scholar 

  42. Lee KJ, Lee KM, Jo S, Kang KW, Park CS (2010) Induction of cereblon by NF-E2-related factor 2 in neuroblastoma cells exposed to hypoxia-reoxygenation. Biochem Biophys Res Commun 399:711–715. doi:10.1016/j.bbrc.2010.08.005

    Article  CAS  PubMed  Google Scholar 

  43. Lee KM, Yang SJ, Kim YD, Choi YD, Nam JH, Choi CS, Choi HS, Park CS (2013) Disruption of the cereblon gene enhances hepatic AMPK activity and prevents high-fat diet-induced obesity and insulin resistance in mice. Diabetes 62:1855–1864. doi:10.2337/db12-1030

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Lee KM, Yang SJ, Park S, Choi YD, Shin HK, Pak JH, Park CS, Kim I (2015) Depletion of the cereblon gene activates the unfolded protein response and protects cells from ER stress-induced cell death. Biochem Biophys Res Commun 458:34–39. doi:10.1016/j.bbrc.2015.01.054

    Article  CAS  PubMed  Google Scholar 

  45. Liu Y, Huang X, He X, Zhou Y, Jiang X, Chen-Kiang S, Jaffrey SR, Xu G (2015) A novel effect of thalidomide and its analogs: suppression of cereblon ubiquitination enhances ubiquitin ligase function. FASEB J 29:4829–4839. doi:10.1096/fj.15-274050

    Article  CAS  PubMed  Google Scholar 

  46. Liu J, Ye J, Zou X, Xu Z, Feng Y, Chen Z, Li Y, Cang Y (2014) CRL4A(CRBN) E3 ubiquitin ligase restricts BK channel activity and prevents epileptogenesis. Nat Commun 5:3924. doi:10.1038/ncomms4924

    CAS  PubMed  Google Scholar 

  47. Lode L, Amiot M, Maiga S, Touzeau C, Menard A, Magrangeas F, Minvielle S, Pellat-Deceunynck C, Bene MC, Moreau P (2013) Cereblon expression in multiple myeloma: not ready for prime time. Br J Haematol 163:282–284. doi:10.1111/bjh.12478

    CAS  PubMed  Google Scholar 

  48. Lopez-Girona A, Heintel D, Zhang LH, Mendy D, Gaidarova S, Brady H, Bartlett JB, Schafer PH, Schreder M, Bolomsky A, Hilgarth B, Zojer N, Gisslinger H, Ludwig H, Daniel T, Jager U, Chopra R (2011) Lenalidomide downregulates the cell survival factor, interferon regulatory factor-4, providing a potential mechanistic link for predicting response. Br J Haematol 154:325–336. doi:10.1111/j.1365-2141.2011.08689.x

    Article  CAS  PubMed  Google Scholar 

  49. Lopez-Girona A, Mendy D, Ito T, Miller K, Gandhi AK, Kang J, Karasawa S, Carmel G, Jackson P, Abbasian M, Mahmoudi A, Cathers B, Rychak E, Gaidarova S, Chen R, Schafer PH, Handa H, Daniel TO, Evans JF, Chopra R (2012) Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide. Leukemia 26:2326–2335. doi:10.1038/leu.2012.119

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Lu G, Middleton RE, Sun H, Naniong M, Ott CJ, Mitsiades CS, Wong KK, Bradner JE, Kaelin WG Jr (2014) The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. Science 343:305–309. doi:10.1126/science.1244917

    Article  CAS  PubMed  Google Scholar 

  51. Lukacs GL, Verkman AS (2012) CFTR: folding, misfolding and correcting the DeltaF508 conformational defect. Trends Mol Med 18:81–91. doi:10.1016/j.molmed.2011.10.003

    Article  CAS  PubMed  Google Scholar 

  52. Menendez-Benito V, Verhoef LG, Masucci MG, Dantuma NP (2005) Endoplasmic reticulum stress compromises the ubiquitin-proteasome system. Hum Mol Genet 14:2787–2799. doi:10.1093/hmg/ddi312

    Article  CAS  PubMed  Google Scholar 

  53. Nguyen TV, Lee JE, Sweredoski MJ, Yang SJ, Jeon SJ, Harrison JS, Yim JH, Lee SG, Handa H, Kuhlman B, Jeong JS, Reitsma JM, Park CS, Hess S, Deshaies RJ (2016) Glutamine triggers acetylation-dependent degradation of glutamine synthetase via the thalidomide receptor cereblon. Mol Cell 61:809–820. doi:10.1016/j.molcel.2016.02.032

    Article  CAS  PubMed  Google Scholar 

  54. Niemeyer MI, Cid LP, Sepulveda FV, Blanz J, Auberson M, Jentsch TJ (2010) No evidence for a role of CLCN2 variants in idiopathic generalized epilepsy. Nat Genet 42:3. doi:10.1038/ng0110-3

    Article  CAS  PubMed  Google Scholar 

  55. Parman T, Wiley MJ, Wells PG (1999) Free radical-mediated oxidative DNA damage in the mechanism of thalidomide teratogenicity. Nat Med 5:582–585. doi:10.1038/8466

    Article  CAS  PubMed  Google Scholar 

  56. Planells-Cases R, Jentsch TJ (2009) Chloride channelopathies. Biochim Biophys Acta 1792:173–189. doi:10.1016/j.bbadis.2009.02.002

    Article  CAS  PubMed  Google Scholar 

  57. Pointon JC, Eagle G, Bailey J, Evans P, Allsup D, Greenman J (2010) Thalidomide enhances cyclophosphamide and dexamethasone-mediated cytotoxicity towards cultured chronic lymphocytic leukaemia cells. Oncol Rep 24:1315–1321. doi:10.3892/or_00000988

    CAS  PubMed  Google Scholar 

  58. Rajadhyaksha AM, Ra S, Kishinevsky S, Lee AS, Romanienko P, DuBoff M, Yang C, Zupan B, Byrne M, Daruwalla ZR, Mark W, Kosofsky BE, Toth M, Higgins JJ (2012) Behavioral characterization of cereblon forebrain-specific conditional null mice: a model for human non-syndromic intellectual disability. Behav Brain Res 226:428–434. doi:10.1016/j.bbr.2011.09.039

    Article  PubMed  Google Scholar 

  59. Richardson SJ, Eve HE, Copplestone JA, Dyer MJ, Rule SA (2010) Activity of thalidomide and lenalidomide in mantle cell lymphoma. Acta Haematol 123:21–29. doi:10.1159/000257990

    Article  CAS  PubMed  Google Scholar 

  60. Russell RR 3rd, Li J, Coven DL, Pypaert M, Zechner C, Palmeri M, Giordano FJ, Mu J, Birnbaum MJ, Young LH (2004) AMP-activated protein kinase mediates ischemic glucose uptake and prevents postischemic cardiac dysfunction, apoptosis, and injury. J Clin Invest 114:495–503. doi:10.1172/JCI19297

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Sawamura N, Wakabayashi S, Matsumoto K, Yamada H, Asahi T (2015) Cereblon is recruited to aggresome and shows cytoprotective effect against ubiquitin-proteasome system dysfunction. Biochem Biophys Res Commun 464:1054–1059. doi:10.1016/j.bbrc.2015.07.068

    Article  CAS  PubMed  Google Scholar 

  62. Schneider RK, Adema V, Heckl D, Jaras M, Mallo M, Lord AM, Chu LP, McConkey ME, Kramann R, Mullally A, Bejar R, Sole F, Ebert BL (2014) Role of casein kinase 1A1 in the biology and targeted therapy of del(5q) MDS. Cancer Cell 26:509–520. doi:10.1016/j.ccr.2014.08.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Schuster SR, Kortuem KM, Zhu YX, Braggio E, Shi CX, Bruins LA, Schmidt JE, Ahmann G, Kumar S, Rajkumar SV, Mikhael J, Laplant B, Champion MD, Laumann K, Barlogie B, Fonseca R, Bergsagel PL, Lacy M, Stewart AK (2014) The clinical significance of cereblon expression in multiple myeloma. Leuk Res 38:23–28. doi:10.1016/j.leukres.2013.08.015

    Article  CAS  PubMed  Google Scholar 

  64. Shaffer AL, Emre NC, Lamy L, Ngo VN, Wright G, Xiao W, Powell J, Dave S, Yu X, Zhao H, Zeng Y, Chen B, Epstein J, Staudt LM (2008) IRF4 addiction in multiple myeloma. Nature 454:226–231. doi:10.1038/nature07064

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Shirwany NA, Zou MH (2010) AMPK in cardiovascular health and disease. Acta Pharmacol Sin 31:1075–1084. doi:10.1038/aps.2010.139

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Shruti S, Clem RL, Barth AL (2008) A seizure-induced gain-of-function in BK channels is associated with elevated firing activity in neocortical pyramidal neurons. Neurobiol Dis 30:323–330. doi:10.1016/j.nbd.2008.02.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Singhal S, Mehta J, Desikan R, Ayers D, Roberson P, Eddlemon P, Munshi N, Anaissie E, Wilson C, Dhodapkar M, Zeddis J, Barlogie B (1999) Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 341:1565–1571. doi:10.1056/NEJM199911183412102

    Article  CAS  PubMed  Google Scholar 

  68. Smith C, Carney JM, Starke-Reed P, Oliver C, Stadtman E, Floyd R, Markesbery W (1991) Excess brain protein oxidation and enzyme dysfunction in normal aging and in Alzheimer disease. Proc Natl Acad Sci 88:10540–10543. doi:10.1073/pnas.88.23.10540

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Smith SM, Grinblatt D, Johnson JL, Niedzwiecki D, Rizzieri D, Bartlett NL, Cheson BD (2008) Thalidomide has limited single-agent activity in relapsed or refractory indolent non-Hodgkin lymphomas: a phase II trial of the cancer and leukemia group B. Br J Haematol 140:313–319. doi:10.1111/j.1365-2141.2007.06937.x

    Article  CAS  PubMed  Google Scholar 

  70. Steinberg GR, Kemp BE (2009) AMPK in health and disease. Physiol Rev 89:1025–1078. doi:10.1152/physrev.00011.2008

    Article  CAS  PubMed  Google Scholar 

  71. Typlt M, Mirkowski M, Azzopardi E, Ruettiger L, Ruth P, Schmid S (2013) Mice with deficient BK channel function show impaired prepulse inhibition and spatial learning, but normal working and spatial reference memory. PLoS ONE 8, e81270. doi:10.1371/journal.pone.0081270

    Article  PubMed  PubMed Central  Google Scholar 

  72. Typlt M, Mirkowski M, Azzopardi E, Ruth P, Pilz PK, Schmid S (2013) Habituation of reflexive and motivated behavior in mice with deficient BK channel function. Front Integr Neurosci 7:79. doi:10.3389/fnint.2013.00079

    Article  PubMed  PubMed Central  Google Scholar 

  73. Viscomi C, Bottani E, Civiletto G, Cerutti R, Moggio M, Fagiolari G, Schon EA, Lamperti C, Zeviani M (2011) In vivo correction of COX deficiency by activation of the AMPK/PGC-1alpha axis. Cell Metab 14:80–90. doi:10.1016/j.cmet.2011.04.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Widmer HA, Rowe IC, Shipston MJ (2003) Conditional protein phosphorylation regulates BK channel activity in rat cerebellar Purkinje neurons. J Physiol 552:379–391. doi:10.1113/jphysiol.2003.046441

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Williams SE, Wootton P, Mason HS, Bould J, Iles DE, Riccardi D, Peers C, Kemp PJ (2004) Hemoxygenase-2 is an oxygen sensor for a calcium-sensitive potassium channel. Science 306:2093–2097. doi:10.1126/science.1105010

    Article  CAS  PubMed  Google Scholar 

  76. Wu H, Zhao C, Gu K, Jiao Y, Hao J, Sun G (2014) Thalidomide plus chemotherapy exhibit enhanced efficacy in the clinical treatment of T-cell non-Hodgkin’s lymphoma: a prospective study of 46 cases. Mol Clin Oncol 2:695–700. doi:10.3892/mco.2014.307

    PubMed  PubMed Central  Google Scholar 

  77. Xin W, Xiaohua N, Peilin C, Xin C, Yaqiong S, Qihan W (2008) Primary function analysis of human mental retardation related gene CRBN. Mol Biol Rep 35:251–256. doi:10.1007/s11033-007-9077-3

    Article  PubMed  Google Scholar 

  78. Xu Q, Hou YX, Langlais P, Erickson P, Zhu J, Shi CX, Luo M, Zhu Y, Xu Y, Mandarino LJ, Stewart K, Chang XB (2016) Expression of the cereblon binding protein argonaute 2 plays an important role for multiple myeloma cell growth and survival. BMC Cancer 16:297. doi:10.1186/s12885-016-2331-0

    Article  PubMed  PubMed Central  Google Scholar 

  79. Yang DY, Ren JH, Guo XN, Guo XL, Cai XY, Guo XF, Zhang JN (2015) Lenalidomide affect expression level of cereblon protein in multiple myeloma cell line RPMI8226. Genet Mol Res 14:13588–13594. doi:10.4238/2015.October.28.19

    CAS  PubMed  Google Scholar 

  80. Zhu YX, Braggio E, Shi CX, Bruins LA, Schmidt JE, Van Wier S, Chang XB, Bjorklund CC, Fonseca R, Bergsagel PL, Orlowski RZ, Stewart AK (2011) Cereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide. Blood 118:4771–4779. doi:10.1182/blood-2011-05-356063

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Zhu YX, Braggio E, Shi CX, Kortuem KM, Bruins LA, Schmidt JE, Chang XB, Langlais P, Luo M, Jedlowski P, LaPlant B, Laumann K, Fonseca R, Bergsagel PL, Mikhael J, Lacy M, Champion MD, Stewart AK (2014) Identification of cereblon-binding proteins and relationship with response and survival after IMiDs in multiple myeloma. Blood 124:536–545. doi:10.1182/blood-2014-02-557819

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Zhu YX, Kortuem KM, Stewart AK (2013) Molecular mechanism of action of immune-modulatory drugs thalidomide, lenalidomide and pomalidomide in multiple myeloma. Leuk Lymphoma 54:683–687. doi:10.3109/10428194.2012.728597

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This study was supported by a grant from the Priority Research Centers Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Education, Science and Technology (2010-0020224, 2015R1A2A1A13001900, and 2015R1D1A1A01057937), Republic of Korea.

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Authors and Affiliations

  1. National Research Laboratory for Mitochondrial Signaling, Department of Physiology, Department of Health Sciences and Technology, BK21 plus Project Team, Cardiovascular and Metabolic Disease Center, College of Medicine, Inje University, Bokji-ro 75, Busanjin-gu, Busan, 47392, South Korea

    Hyoung Kyu Kim, Tae Hee Ko, Bayalagmaa Nyamaa, Sung Ryul Lee, Nari Kim, Kyung Soo Ko, Byoung Doo Rhee & Jin Han

  2. Department of Integrated Biomedical Science, College of Medicine, Inje University, Busan, South Korea

    Hyoung Kyu Kim & Sung Ryul Lee

  3. School of Life Sciences and National Leading Research Laboratory for Ion Channels, Gwangju Institute Science and Technology, Gwangju, 500-712, South Korea

    Chul-Seung Park

  4. Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium

    Bernd Nilius

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  1. Hyoung Kyu Kim
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Correspondence to Jin Han.

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Kim, H.K., Ko, T.H., Nyamaa, B. et al. Cereblon in health and disease. Pflugers Arch - Eur J Physiol 468, 1299–1309 (2016). https://doi.org/10.1007/s00424-016-1854-1

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