Cereblon
Encyclopedia
Cereblon is a protein
that in humans is encoded by the CRBN gene
. 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.
binds and inactivates cereblon, which leads to a teratogenic effect on fetal development
. 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from 1957 until 1961 but was withdrawn from the market after it was discovered that it caused birth defects. It is estimated that 10,000 to 20,000 children were affected.
possibly as a result of dysregulation of calcium-activated potassium channels in the brain (see below) during development.
complex with damaged DNA binding protein 1 (DDB1
), Cullin-4A (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 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 embryo
s.
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.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that in humans is encoded by the CRBN gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
. The gene that encodes the cereblon protein is found on the human chromosome 3
Chromosome 3 (human)
Chromosome 3 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 3 spans almost 200 million base pairs and represents about 6.5 percent of the total DNA in cells....
, on the short arm at position p26.3 from base pair
Base pair
In molecular biology and genetics, the linking between two nitrogenous bases on opposite complementary DNA or certain types of RNA strands that are connected via hydrogen bonds is called a base pair...
3,190,676 to base pair 3,221,394. CRBN orthologs are highly conserved from plants to humans.
Birth defects
It is believed that the drug thalidomideThalidomide
Thalidomide was introduced as a sedative drug in the late 1950s that was typically used to cure morning sickness. In 1961, it was withdrawn due to teratogenicity and neuropathy. There is now a growing clinical interest in thalidomide, and it is introduced as an immunomodulatory agent used...
binds and inactivates cereblon, which leads to a teratogenic effect on fetal development
Fetal development
Prenatal or antenatal development is the process in which a human embryo or fetus gestates during pregnancy, from fertilization until birth. Often, the terms fetal development, foetal development, or embryology are used in a similar sense.After fertilization the embryogenesis starts...
. Thalidomide was used as a treatment for morning sickness
Morning sickness
Morning sickness, also called nausea gravidarum, nausea, vomiting of pregnancy , or pregnancy sickness is a condition that affects more than half of all pregnant women. Related to increased oestrogen levels, a similar form of nausea is also seen in some women who use hormonal contraception or...
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.
Mental retardation
Mutations in the CRBN gene are associated with autosomal recessive nonsyndromic mental retardationMental retardation
Mental retardation is a generalized disorder appearing before adulthood, characterized by significantly impaired cognitive functioning and deficits in two or more adaptive behaviors...
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 ubiquitin ligaseUbiquitin ligase
A ubiquitin ligase is a protein that in combination with an E2 ubiquitin-conjugating enzyme causes the attachment of ubiquitin to a lysine on a target protein via an isopeptide bond; the E3 ubiquitin ligase targets specific protein substrates for degradation by the proteasome...
complex with damaged DNA binding protein 1 (DDB1
DDB1
DNA damage-binding protein 1 is a protein that in humans is encoded by the DDB1 gene.- Function :This gene encodes the large subunit of DNA damage-binding protein which is a heterodimer composed of a large and a small subunit. This protein functions in nucleotide excision repair...
), Cullin-4A (CUL4A
CUL4A
Cullin-4A is a protein that in humans is encoded by the CUL4A gene.-Interactions:CUL4A has been shown to interact with Merlin, DDB2, CAND1, RBX1, DDB1 and P21.-Further reading:...
), and regulator of cullins 1 (ROC1
RBX1
RING-box protein 1 is a protein that in humans is encoded by the RBX1 gene.-Interactions:RBX1 has been shown to interact with CUL4A, CAND1, CUL1, CUL2, P70-S6 Kinase 1, DCUN1D1, CUL5 and CUL7.-Further reading:...
). 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
Fibroblast growth factor 8 is a protein that in humans is encoded by the FGF8 gene.-External links:*...
). FGF8 in turn regulates a number of developmental
Human development (biology)
Human development is the process of growing to maturity. In biological terms, this entails growth from a one-celled zygote to an adult human being.- Biological development:...
processes, such as limb and auditory vesicle
Auditory vesicle
When the mouth of the auditory pit is closed, and thus a shut sac, the auditory vesicle , is formed; from it the epithelial lining of the membranous labyrinth is derived....
formation. The net result is that this ubiquitin ligase complex is important for limb outgrowth in embryo
Embryo
An embryo is a multicellular diploid eukaryote in its earliest stage of development, from the time of first cell division until birth, hatching, or germination...
s.
In the absence of cereblon, DDB1 forms a complex with DDB2
DDB2
DNA damage-binding protein 2 is a protein that in humans is encoded by the DDB2 gene.-Interactions:DDB2 has been shown to interact with CUL4A, CUL4B and DDB1.-External Links:* -Further reading:...
that functions as a DNA damage-binding protein
DNA damage-binding protein
DNA damage-binding protein is a protein complex that is responsible for repair of UV-damaged DNA. This complex is composed of two protein subunits, a large subunit DDB1 and a small subunit DDB2. This complex functions in nucleotide excision repair....
. Furthermore, cereblon and DDB2 bind to DDB1 in a competitive manner.