Cereblon

Cereblon
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols CRBN ; MRT2; MRT2A
External IDs OMIM: 609262 MGI: 1913277 HomoloGene: 9461 GeneCards: CRBN Gene
EC number 3.4.-
Orthologs
Species Human Mouse
Entrez 51185 58799
Ensembl ENSG00000113851 ENSMUSG00000005362
UniProt Q96SW2 Q8C7D2
RefSeq (mRNA) NM_001173482 NM_021449
RefSeq (protein) NP_001166953 NP_067424
Location (UCSC) Chr 3:
3.15 – 3.18 Mb		 Chr 6:
106.78 – 106.8 Mb
PubMed search

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 was believed that the drug thalidomide binds and inactivates cereblon, which leads to an antiproliferative effect on myeloma cells and 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on fetal development.[2][3][4][5] Thalidomide was used as a treatment for morning sickness from 1957 until 1961 but was withdrawn from the market after it was discovered that it caused birth defects.[6] It is estimated that 10,000 to 20,000 children were affected.[7] However, the finding that cereblon inhibition is responsible for the teratogenic activity of thalidomide in the chick and zebrafish was cast into doubt due to a 2013 report that pomalidomide (a more potent thalidomide analog) does not cause teratogenic effects in these same model systems even though it is a stronger cereblon inhibitor than thalidomide is.[8][9]

Intellectual disability

Mutations in the CRBN gene are associated with autosomal recessive nonsyndromic intellectual disability,[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).[10] This complex ubiquitinates a number of other proteins. Through a mechanism which has not been completely elucidated, this ubiquitination results in reduced levels of fibroblast growth factor 8 (FGF8) and fibroblast growth factor 10 (FGF10). 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 potassium channels

Cereblon binds to the large-conductance calcium-activated potassium channel (KCNMA1) and regulates its activity.[11][12] Moreover, mice lacking this channel develop neurological disorders.[13]

References

  1. 1 2 3 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. doi:10.1212/01.wnl.0000146196.01316.a2. PMC 1201536. PMID 15557513.
  2. 1 2 3 4 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. Lay summary – BBC News.
  3. ↑ Carl Zimmer (March 15, 2010). "Answers Begin to Emerge on How Thalidomide Caused Defects". New York Times. 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. Retrieved 2010-03-11.
  5. ↑ Moisse K (2010-03-11). "Researchers Gain New Insights into the Mystery of Thalidomide-Caused Birth Defect". Scientific American. Retrieved 2010-03-11.
  6. ↑ Anon. "Thalidomide - A Second Chance? - programme summary". BBC. Retrieved 2009-05-01.
  7. ↑ Anon. "Born Freak". Happy Birthday Thalidomide. Channel 4. Retrieved 2009-05-01.
  8. ↑ Mahony C, Erskine L, Niven J, Greig NH, Figg WD, Vargesson N (2013). "Pomalidomide is nonteratogenic in chicken and zebrafish embryos and nonneurotoxic in vitro". Proc. Natl. Acad. Sci. U.S.A. 110 (31): 12703–8. doi:10.1073/pnas.1307684110. PMC 3732931. PMID 23858438.
  9. ↑ 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 (11): 2326–35. doi:10.1038/leu.2012.119. PMC 3496085. PMID 22552008.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ 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.

Further reading

External links

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