Cereblon is a
protein that in humans is encoded by the CRBNgene.[5] 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.[5]
Function
Ubiquitination 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).[6] This complex
ubiquitinates a number of other proteins and marks them for degradation via the
proteasome. 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.[7]
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.[7]
Regulation of potassium channels
Cereblon binds to the large-conductance calcium-activated potassium channel (
KCNMA1) and regulates its activity.[8][9] Moreover, mice lacking this channel develop neurological disorders.[10]
Clinical significance
Birth defects
The drug
thalidomide binds to cereblon and changes which substrates can be degraded by it, which leads to an antiproliferative effect on myeloma cells and possibly the
teratogenic effect on
fetal development.[7][11][12][13] 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morning sickness from 1957 until 1961 but was withdrawn from the market after it was discovered that it caused birth defects.[14] It is estimated that 10,000 to 20,000 children were affected.[15] However, the idea that cereblon modulation 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 analogue) does not cause teratogenic effects in these same model systems even though it binds with cereblon more strongly than thalidomide.[16][17]
Intellectual disability
Mutations in the CRBN gene are associated with
autosomal recessive nonsyndromic
intellectual disability,[5] possibly as a result of dysregulation of calcium-activated potassium channels in the brain (see below) during development.[7]
Targeted protein degradation
Based on the finding that thalidomide and related analogues bind CRBN, heterobifunctional molecules were designed linking thalidomide to ligands for other proteins of interest.[18][19] These molecules, termed
proteolysis targeting chimeras (PROTACs) or protein degraders, recruit CRBN to a protein of interest, leading to its ubiquitination and subsequent degradation. This technology is being explored in clinical trials by a number of biotechnology companies such as Arvinas, C4 Therapeutics, and Kymera Therapeutics.[20]
^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.
PMID16045448.
S2CID20578294.
^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.
PMID18414909.
S2CID20729122.
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.
PMID17380424.
S2CID5810442.
Cereblon is a
protein that in humans is encoded by the CRBNgene.[5] 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.[5]
Function
Ubiquitination 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).[6] This complex
ubiquitinates a number of other proteins and marks them for degradation via the
proteasome. 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.[7]
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.[7]
Regulation of potassium channels
Cereblon binds to the large-conductance calcium-activated potassium channel (
KCNMA1) and regulates its activity.[8][9] Moreover, mice lacking this channel develop neurological disorders.[10]
Clinical significance
Birth defects
The drug
thalidomide binds to cereblon and changes which substrates can be degraded by it, which leads to an antiproliferative effect on myeloma cells and possibly the
teratogenic effect on
fetal development.[7][11][12][13] 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.[14] It is estimated that 10,000 to 20,000 children were affected.[15] However, the idea that cereblon modulation 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 analogue) does not cause teratogenic effects in these same model systems even though it binds with cereblon more strongly than thalidomide.[16][17]
Intellectual disability
Mutations in the CRBN gene are associated with
autosomal recessive nonsyndromic
intellectual disability,[5] possibly as a result of dysregulation of calcium-activated potassium channels in the brain (see below) during development.[7]
Targeted protein degradation
Based on the finding that thalidomide and related analogues bind CRBN, heterobifunctional molecules were designed linking thalidomide to ligands for other proteins of interest.[18][19] These molecules, termed
proteolysis targeting chimeras (PROTACs) or protein degraders, recruit CRBN to a protein of interest, leading to its ubiquitination and subsequent degradation. This technology is being explored in clinical trials by a number of biotechnology companies such as Arvinas, C4 Therapeutics, and Kymera Therapeutics.[20]
^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.
PMID16045448.
S2CID20578294.
^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.
PMID18414909.
S2CID20729122.
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.
PMID17380424.
S2CID5810442.