Cereblon in health and disease

Abstract

Cereblon (CRBN) is a substrate receptor of the E3 ubiquitin ligase complex that has been linked to autosomal recessive non-syndromic mental retardation. Several key findings suggest diverse roles of CRBN, including its regulation of the large-conductance calcium- and voltage-activated potassium (BKCa) channels, regulation of thalidomide-binding proteins, and mediation of lenalidomide treatment in multiple myeloma. Recent studies also indicate that CRBN is involved in energy metabolism and negatively regulates AMP-activated protein kinase signaling. Mice with genetic depletion of CRBN are resistant to various stress conditions including a high-fat diet, endoplasmic reticulum stress, ischemia/reperfusion injury, and alcohol-related liver damage. In this review, we discuss the various roles of CRBN in human health and disease and suggest avenues for further research to enhance our basic knowledge and clinical application of CRBN.

Induction of SIRT1 by melatonin improves alcohol‐mediated oxidative liver injury by disrupting the CRBN‐YY1‐CYP2E1 signaling pathway

“…As previously described, CRBN is closely associated with obesity and insulin resistance in nonalcoholic fatty liver disease models and it also regulates a variety of biological processes, including ER stress, mitochondrial biogenesis, and lipogenesis. [21][22][23] Our previous study demonstrated that the increase in CRBN by alcohol feeding exacerbated metabolic dysfunction by promoting hepatic steatosis and inflammation. 23 However, the role of CRBN in alcohol-mediated liver injury has not been investigated.…”

“…CRBN is a substrate receptor of the E3 ubiquitin ligase complex that has been associated to mild autosomal recessive nonsyndromic mental retardation. It is highly expressed in the brain and is also present in diverse tissues, including skeletal muscle, kidney, and liver . Our previous studies have demonstrated that disruption of CRBN improves hepatic steatosis and inflammation via AMPK activation in mouse models of nonalcoholic and alcoholic fatty liver diseases .…”

“…It is highly expressed in the brain and is also present in diverse tissues, including skeletal muscle, kidney, and liver. 20,21 Our previous studies have demonstrated that disruption of CRBN improves hepatic steatosis and inflammation via AMPK activation in mouse models of nonalcoholic and alcoholic fatty liver diseases. 22,23 In addition, Ying Yang 1 (YY1) is a multifunctional zinc-finger transcription factor of the polycomb protein family which can bind to its signature binding motif (CCATNTT).…”

Introductory Chapter: Progress in Myelodysplastic Syndrome Area

“…Several researchers confirmed CRBN as target of lenalidomide in multiple myeloma (MM), lymphoma, chronic lymphocytic leukemia, and del(5q) MDS [48]. CRBN is the ubiquitously expressed 51 kDa protein with a putative role in cerebral development, especially memory and learning [49,50]. Our group found that del(5q) MDS patients (the so-called 5q minus syndrome) have higher levels of full-length CRBN mRNA than other patients with lower risk MDS, linking higher levels of a known lenalidomide target CRBN and del(5q) MDS subgroup known to be especially sensitive to lenalidomide [51].…”

Immunomodulatory drugs and their therapeutic effect in hematological malignancies through cereblon

“…GS is important for de novo synthesis of glutamine and functions tn detoxification of glutamate and ammonia. GS is associated with diseases including cancer, Alzheimer´s disease and Huntington disease [89].…”