Int J Biochem Mol Biol 2011;2(3):287-294
What is the functional role of the thalidomide binding protein cereblon?
Xiu-bao Chang, A. Keith Stewart
Mayo Clinic College of Medicine, Mayo Clinic Arizona, Scottsdale, AZ 85259, USA.
Received August 18, 2011; accepted September 3, 2011; Epub September 10, 2011; Published August 30, 2011
Abstract: It has been found that nonsense mutation R419X of cereblon (CRBN) is associated with autosomal recessive non-syndromic
mental retardation. Further experiments showed that CRBN binds to the cytosolic C-terminus of large-conductance Ca++ activated potassium
channel (BKCa) α-subunit and the cytosolic C-terminus of a voltage-gated chloride channel-2 (ClC-2), suggesting that CRBN may play a role in
memory and learning via regulating the assembly and surface expression of BKCa and ClC-2 channels. In addition, it has also been found that
CRBN directly interacts with the α1 subunit of AMP-activated protein kinase (AMPK) and prevents formation of a functional holoenzyme with
regulatory subunits β and γ. Since AMPK is a master sensor of energy balance that inhibits ATP-consuming anabolic pathways and increases
ATP-producing catabolic pathways, binding of CRBN with α1 subunit of AMPK may play a role in these pathways by regulating the function of
AMPK. Furthermore, CRBN interacts with damaged DNA binding protein 1 and forms an E3 ubiquitin ligase complex with Cullin 4 where it
functions as a substrate receptor in which the proteins recognized by CRBN might be ubiquitinated and degraded by proteasomes.
Proteasome-mediated degradation of unneeded or damaged proteins plays a very important role in maintaining regular function of a cell, such
as cell survival, dividing, proliferation and growth. Intriguingly, a new role for CRBN has been identified, i.e, the binding of immunomodulatory
drugs (IMiDs), e.g. thalidomide, to CRBN has now been associated with teratogenicity and also the cytotoxicity of IMiDs, including lenalidomide,
which are widely used to treat multiple myeloma patients. CRBN likely plays an important role in binding, ubiquitination and degradation of
factors involved in maintaining function of myeloma cells. These new findings regarding the role of CRBN in IMiD action will stimulate intense
investigation of CRBN's downstream factors involved in maintaining regular function of a cell. (IJBMB1108002)
Keywords: CRBN, ClC-2, AMPK, BKCa, DDB1, Cul4A, E3 ubiquitin ligase
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Mayo Clinic College of Medicine
Mayo Clinic Arizona, Scottsdale, AZ 85259, USA.
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