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词条 Cereblon
释义

  1. Clinical significance

      Birth defects   Intellectual disability 

  2. Function

      Ubiquitinization and role in development    Regulation of potassium channels  

  3. References

  4. Further reading

  5. External links

{{Infobox_gene}}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on fetal development.[2][3][4][5] Thalidomide was used as a treatment for morning sickness from 1957 until 1961 but was withdrawn from the market after it was discovered that it caused birth defects.[6] It is estimated that 10,000 to 20,000 children were affected.[7] However, the finding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 {{cite journal |vauthors=Higgins JJ, Pucilowska J, Lombardi RQ, Rooney JP | title = A mutation in a novel ATP-dependent Lon protease gene in a kindred with mild mental retardation | journal = Neurology | volume = 63 | issue = 10 | pages = 1927–31 |date=November 2004 | pmid = 15557513 | pmc = 1201536 | doi = 10.1212/01.wnl.0000146196.01316.a2| url = }}
2. ^1 2 3 {{cite journal |vauthors=Ito T, Ando H, Suzuki T, Ogura T, Hotta K, Imamura Y, Yamaguchi Y, Handa H | title = Identification of a primary target of thalidomide teratogenicity | journal = Science | volume = 327 | issue = 5971 | pages = 1345–1350 | year = 2010 | month = | pmid = 20223979 | pmc = | doi = 10.1126/science.1177319 | url = http://www.sciencemag.org/cgi/content/abstract/327/5971/1345 | laysummary = http://news.bbc.co.uk/1/hi/sci/tech/8562998.stm | laysource = BBC News }}
3. ^{{cite news |author=Carl Zimmer |title=Answers Begin to Emerge on How Thalidomide Caused Defects |url=https://www.nytimes.com/2010/03/16/science/16limb.html?ref=science&pagewanted=all |quote=As they report in the current issue of Science, a protein known as cereblon latched on tightly to the thalidomide.|work=The New York Times |date= March 15, 2010 |accessdate=2010-03-21 }}
4. ^{{cite web | url = http://www.rsc.org/chemistryworld/News/2010/March/11031001.asp | title = Thalidomide binding protein revealed | date = 2010-03-11 | format = | work = Chemistry World | publisher = Royal Society of Chemistry | pages = | language = | archiveurl = | archivedate = | quote = | accessdate = 2010-03-11 }}
5. ^{{cite web | url = http://www.scientificamerican.com/article.cfm?id=thalidomide-target-identified | title = Researchers Gain New Insights into the Mystery of Thalidomide-Caused Birth Defect | author = Moisse K | date = 2010-03-11 | format = | website = | publisher = Scientific American | pages = | language = | archiveurl = | archivedate = | quote = | accessdate = 2010-03-11 }}
6. ^{{cite web|url=http://www.bbc.co.uk/science/horizon/2004/thalidomide.shtml|title=Thalidomide - A Second Chance? - programme summary|last=Anon|publisher=BBC|accessdate=2009-05-01}}
7. ^{{cite web|url=http://www.channel4.com/life/microsites/B/bornfreak/birthday.html|title=Born Freak|last=Anon|work=Happy Birthday Thalidomide|publisher=Channel 4|accessdate=2009-05-01}}
8. ^{{cite journal |vauthors=Mahony C, Erskine L, Niven J, Greig NH, Figg WD, Vargesson N | title = Pomalidomide is nonteratogenic in chicken and zebrafish embryos and nonneurotoxic in vitro | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 110 | issue = 31 | pages = 12703–8 | year = 2013 | pmid = 23858438 | pmc = 3732931 | doi = 10.1073/pnas.1307684110 | url = }}
9. ^{{cite journal |vauthors=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 | title = Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide | journal = Leukemia | volume = 26 | issue = 11 | pages = 2326–35 | year = 2012 | pmid = 22552008 | pmc = 3496085 | doi = 10.1038/leu.2012.119 }}
10. ^{{cite journal |vauthors=Angers S, Li T, Yi X, MacCoss MJ, Moon RT, Zheng N | title = Molecular architecture and assembly of the DDB1-CUL4A ubiquitin ligase machinery | journal = Nature | volume = 443 | issue = 7111 | pages = 590–3 |date=October 2006 | pmid = 16964240 | doi = 10.1038/nature05175 | url = }}
11. ^{{cite journal |vauthors=Jo S, Lee KH, Song S, Jung YK, Park CS | title = Identification and functional characterization of cereblon as a binding protein for large-conductance calcium-activated potassium channel in rat brain | journal = J. Neurochem. | volume = 94 | issue = 5 | pages = 1212–24 |date=September 2005 | pmid = 16045448 | doi = 10.1111/j.1471-4159.2005.03344.x | url = }}
12. ^{{cite journal |vauthors=Higgins JJ, Hao J, Kosofsky BE, Rajadhyaksha AM | title = Dysregulation of large-conductance Ca2+-activated K+ channel expression in nonsyndromal mental retardation due to a cereblon p.R419X mutation | journal = Neurogenetics | volume = 9 | issue = 3 | pages = 219–23 |date=July 2008 | pmid = 18414909 | doi = 10.1007/s10048-008-0128-2 | url = }}
13. ^{{cite journal |vauthors=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 | title = Cerebellar ataxia and Purkinje cell dysfunction caused by Ca2+-activated K+ channel deficiency | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 101 | issue = 25 | pages = 9474–8 |date=June 2004 | pmid = 15194823 | pmc = 439001 | doi = 10.1073/pnas.0401702101 | url = }}

Further reading

{{refbegin | 2}}
  • {{cite journal |vauthors=Higgins JJ, Rosen DR, Loveless JM |title=A gene for nonsyndromic mental retardation maps to chromosome 3p25-pter |journal=Neurology |volume=55 |issue= 3 |pages= 335–40 |year= 2000 |pmid= 10932263 |doi= 10.1212/wnl.55.3.335|display-authors=etal}}
  • {{cite journal |vauthors=Ota T, Suzuki Y, Nishikawa T |title=Complete sequencing and characterization of 21,243 full-length human cDNAs |journal=Nat. Genet. |volume=36 |issue= 1 |pages= 40–5 |year= 2004 |pmid= 14702039 |doi= 10.1038/ng1285 |display-authors=etal}}
  • {{cite journal |vauthors=Xin W, Xiaohua N, Peilin C |title=Primary function analysis of human mental retardation related gene CRBN |journal=Mol. Biol. Rep. |volume=35 |issue= 2 |pages= 251–6 |year= 2008 |pmid= 17380424 |doi= 10.1007/s11033-007-9077-3 |display-authors=etal}}
  • {{cite journal |vauthors=Hu RM, Han ZG, Song HD |title=Gene expression profiling in the human hypothalamus-pituitary-adrenal axis and full-length cDNA cloning |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=97 |issue= 17 |pages= 9543–8 |year= 2000 |pmid= 10931946 |doi= 10.1073/pnas.160270997 |pmc=16901 |display-authors=etal}}
  • {{cite journal |vauthors=Sowa ME, Bennett EJ, Gygi SP, Harper JW |title=Defining the Human Deubiquitinating Enzyme Interaction Landscape |journal=Cell |volume=138 |issue= 2 |pages= 389–403 |year= 2009 |pmid= 19615732 |doi= 10.1016/j.cell.2009.04.042 |pmc=2716422 }}
{{refend}}

External links

  • {{MeSH name|CRBN+protein,+human|3=CRBN protein, human}}
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