Cereblon

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

Birth defects
It was believed that the drug is_associated_with::thalidomide binds and inactivates cereblon, which leads to an antiproliferative effect on myeloma cells and a is_associated_with::teratogenic effect on is_associated_with::fetal development. Thalidomide was used as a treatment for is_associated_with::morning sickness from 1957 until 1961 but was withdrawn from the market after it was discovered that it caused birth defects. It is estimated that 10,000 to 20,000 children were affected. 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 is_associated_with::pomaliomide (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.

Mental retardation
Mutations in the CRBN gene are associated with autosomal recessive nonsyndromic is_associated_with::mental retardation, possibly as a result of dysregulation of calcium-activated potassium channels in the brain (see below) during development.

Ubiquitinization and role in development
Cereblon forms an E3 is_associated_with::ubiquitin ligase complex with damaged DNA binding protein 1 (is_associated_with::DDB1), Cullin-4A (is_associated_with::CUL4A), and regulator of cullins 1 (ROC1). 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 (is_associated_with::FGF8) and fibroblast growth factor 10 (is_associated_with::FGF10). FGF8 in turn regulates a number of developmental processes, such as limb and is_associated_with::auditory vesicle formation. The net result is that this ubiquitin ligase complex is important for limb outgrowth in is_associated_with::embryos.

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

Regulation of potassium channels
Cereblon binds to the large-conductance calcium-activated potassium channel (KCNMA1) and regulates its activity. Moreover, mice lacking this channel develop neurological disorders.