Cereblon

Cereblon
Identifiers
Symbols	CRBN; DKFZp781K0715; MGC27358; MRT2A
External IDs	OMIM: 609262 MGI: 1913277 HomoloGene: 9461 GeneCards: CRBN Gene
EC number	3.4.-
Gene Ontology Molecular function • ATP-dependent peptidase activity • protein binding Cellular component • nucleus • cytoplasm • membrane • Cul4A-RING ubiquitin ligase complex Biological process • proteolysis • protein ubiquitination • proteasomal ubiquitin-dependent protein catabolic process Sources: Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	51185	58799
Ensembl	ENSG00000113851	ENSMUSG00000005362
UniProt	Q96SW2	Q8C7D2
RefSeq (mRNA)	NM_001173482.1	NM_021449
RefSeq (protein)	NP_001166953.1	NP_780566
Location (UCSC)	Chr 3: 3.19 – 3.22 Mb	Chr 6: 106.73 – 106.75 Mb
PubMed search	[1]	[2]

Cereblon is a protein that in humans is encoded by the CRBN gene.^[1] The gene that encodes the cereblon protein is found on the human chromosome 3, on the short arm at position p26.3 from base pair 3,190,676 to base pair 3,221,394. CRBN orthologs are highly conserved from plants to humans.^[1]

Clinical significance

Birth defects

It is believed that the drug thalidomide binds and inactivates cereblon, which leads to a teratogenic effect on fetal development.^[2][3][4][5] Thalidomide was used as a treatment for morning sickness from 1957 until 1961 but was withdrawn from the market after it was discovered that it caused birth defects.^[6] It is estimated that 10,000 to 20,000 children were affected.^[7]

Mental retardation

Mutations in the CRBN gene are associated with autosomal recessive nonsyndromic mental retardation^[1] possibly as a result of dysregulation of calcium-activated potassium channels in the brain (see below) during development.^[2]

Function

Ubiquitinization and role in development

Cereblon forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1), Cullin-4A (CUL4A), and regulator of cullins 1 (ROC1).^[8] This complex ubiquitinates a number of other proteins. Through a mechanism which has not been completely elucidated, this ubiquitination results in increased levels of fibroblast growth factor 8 (FGF8). FGF8 in turn regulates a number of developmental processes, such as limb and auditory vesicle formation. The net result is that this ubiquitin ligase complex is important for limb outgrowth in embryos.^[2]

In the absence of cereblon, DDB1 forms a complex with DDB2 that functions as a DNA damage-binding protein. Furthermore, cereblon and DDB2 bind to DDB1 in a competitive manner.^[2]

Regulation of calcium channels

Cereblon binds to the large-conductance calcium-activated potassium channel (KCNMA1) and regulates its activity.^[9][10] Moreover, mice lacking this channel develop neurological disorders.^[11]

References

1. ^ ^{a b c} Higgins JJ, Pucilowska J, Lombardi RQ, Rooney JP (November 2004). "A mutation in a novel ATP-dependent Lon protease gene in a kindred with mild mental retardation". Neurology 63 (10): 1927–31. PMC 1201536. PMID 15557513. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1201536. 
2. ^ ^{a b c d} 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 (5971): 1345–1350. doi:10.1126/science.1177319. PMID 20223979. http://www.sciencemag.org/cgi/content/abstract/327/5971/1345. Lay summary – BBC News. 
3. ^ Carl Zimmer (March 15, 2010). "Answers Begin to Emerge on How Thalidomide Caused Defects". New York Times. http://www.nytimes.com/2010/03/16/science/16limb.html?ref=science&pagewanted=all. Retrieved 2010-03-21. "As they report in the current issue of Science, a protein known as cereblon latched on tightly to the thalidomide." 
4. ^ "Thalidomide binding protein revealed". Chemistry World. Royal Society of Chemistry. 2010-03-11. http://www.rsc.org/chemistryworld/News/2010/March/11031001.asp. Retrieved 2010-03-11. 
5. ^ Moisse K (2010-03-11). "Researchers Gain New Insights into the Mystery of Thalidomide-Caused Birth Defect". Scientific American. http://www.scientificamerican.com/article.cfm?id=thalidomide-target-identified. Retrieved 2010-03-11. 
6. ^ Anon. "Thalidomide - A Second Chance? - programme summary". BBC. http://www.bbc.co.uk/science/horizon/2004/thalidomide.shtml. Retrieved 2009-05-01. 
7. ^ Anon. "Born Freak". Happy Birthday Thalidomide. Channel 4. http://www.channel4.com/life/microsites/B/bornfreak/birthday.html. Retrieved 2009-05-01. 
8. ^ Angers S, Li T, Yi X, MacCoss MJ, Moon RT, Zheng N (October 2006). "Molecular architecture and assembly of the DDB1-CUL4A ubiquitin ligase machinery". Nature 443 (7111): 590–3. doi:10.1038/nature05175. PMID 16964240. 
9. ^ Jo S, Lee KH, Song S, Jung YK, Park CS (September 2005). "Identification and functional characterization of cereblon as a binding protein for large-conductance calcium-activated potassium channel in rat brain". J. Neurochem. 94 (5): 1212–24. doi:10.1111/j.1471-4159.2005.03344.x. PMID 16045448. 
10. ^ Higgins JJ, Hao J, Kosofsky BE, Rajadhyaksha AM (July 2008). "Dysregulation of large-conductance Ca2+-activated K+ channel expression in nonsyndromal mental retardation due to a cereblon p.R419X mutation". Neurogenetics 9 (3): 219–23. doi:10.1007/s10048-008-0128-2. PMID 18414909. 
11. ^ Sausbier M, Hu H, Arntz C, Feil S, Kamm S, Adelsberger H, Sausbier U, Sailer CA, Feil R, Hofmann F, Korth M, Shipston MJ, Knaus HG, Wolfer DP, Pedroarena CM, Storm JF, Ruth P (June 2004). "Cerebellar ataxia and Purkinje cell dysfunction caused by Ca2+-activated K+ channel deficiency". Proc. Natl. Acad. Sci. U.S.A. 101 (25): 9474–8. doi:10.1073/pnas.0401702101. PMC 439001. PMID 15194823. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=439001. 

Further reading

• Higgins JJ, Rosen DR, Loveless JM, et al. (2000). "A gene for nonsyndromic mental retardation maps to chromosome 3p25-pter". Neurology 55 (3): 335–40. PMID 10932263. 
• Ota T, Suzuki Y, Nishikawa T, et al. (2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs". Nat. Genet. 36 (1): 40–5. doi:10.1038/ng1285. PMID 14702039. 
• Xin W, Xiaohua N, Peilin C, et al. (2008). "Primary function analysis of human mental retardation related gene CRBN". Mol. Biol. Rep. 35 (2): 251–6. doi:10.1007/s11033-007-9077-3. PMID 17380424. 
• Hu RM, Han ZG, Song HD, et al. (2000). "Gene expression profiling in the human hypothalamus-pituitary-adrenal axis and full-length cDNA cloning". Proc. Natl. Acad. Sci. U.S.A. 97 (17): 9543–8. doi:10.1073/pnas.160270997. PMC 16901. PMID 10931946. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=16901. 
• Sowa ME, Bennett EJ, Gygi SP, Harper JW (2009). "Defining the Human Deubiquitinating Enzyme Interaction Landscape". Cell 138 (2): 389–403. doi:10.1016/j.cell.2009.04.042. PMC 2716422. PMID 19615732. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2716422. 

External links

• MeSH CRBN protein, human