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Half a century ago, thalidomide was widely prescribed to pregnant women as a sedative but was found to be teratogenic, causing multiple birth defects. Today, thalidomide is still used in the treatment of leprosy and multiple myeloma, although how it causes limb malformation and other developmental defects is unknown. Here, we identified cereblon (CRBN) as a(More)
Cereblon (CRBN), the molecular target of lenalidomide and pomalidomide, is a substrate receptor of the cullin ring E3 ubiquitin ligase complex, CRL4(CRBN) . T cell co-stimulation by lenalidomide or pomalidomide is cereblon dependent: however, the CRL4(CRBN) substrates responsible for T cell co-stimulation have yet to be identified. Here we demonstrate that(More)
The Cul4–Rbx1–DDB1–Cereblon E3 ubiquitin ligase complex is the target of thalidomide, lenalidomide and pomalidomide, therapeutically important drugs for multiple myeloma and other B-cell malignancies. These drugs directly bind Cereblon (CRBN) and promote the recruitment of substrates Ikaros (IKZF1) and Aiolos (IKZF3) to the E3 complex, thus leading to(More)
Fifty years ago, prescription of the sedative thalidomide caused a worldwide epidemic of multiple birth defects. The drug is now used in the treatment of leprosy and multiple myeloma. However, its use is limited due to its potent teratogenic activity. The mechanism by which thalidomide causes limb malformations and other developmental defects is a(More)
Muscle cell differentiation, or myogenesis, is a well-characterized process and involves the expression of specific sets of genes in an orderly manner. A prerequisite for myogenesis is the exit from the cell cycle, which is associated with the up-regulation of the tumor suppressor Rb. In this study, we set to investigate the regulatory mechanism of the Rb(More)
BACKGROUND Previously, we reported that Sema3A, one of the secreted repulsive axon guidance molecules, CRMP (collapsin response mediator protein)-2, a putative intracellular signalling molecule for Sema3A and Sema3A receptor neuropilin-1 are expressed in the developing lung. Sema3A inhibits branching morphogenesis of embryonic lung in organ culture. (More)
Elucidating the mechanism of action of bioactive compounds, such as commonly used pharmaceutical drugs and biologically active natural products, in the cells and the living body is important in drug discovery research. To this end, isolation and identification of target protein(s) for the bioactive compound are essential in understanding its function fully.(More)
Thalidomide was originally developed in 1954 as a sedative that was commonly used to ameliorate morning sickness. However, thalidomide exposure during the first trimester of pregnancy caused multiple birth defects (e.g. phocomelia and amelia), affecting ≈ 10,000 children worldwide in the late 1950s and early 1960s. Thalidomide is now recognized as a(More)
Immunomodulatory drugs bind to cereblon (CRBN) to confer differentiated substrate specificity on the CRL4(CRBN) E3 ubiquitin ligase. Here we report the identification of a new cereblon modulator, CC-885, with potent anti-tumour activity. The anti-tumour activity of CC-885 is mediated through the cereblon-dependent ubiquitination and degradation of the(More)
Cereblon is implicated in mild mental retardation and proved to bind to a teratogenic hypnotic, thalidomide. Here, we determined cereblon mRNA distributions in adult mouse brain. Almost all neurons expressed cereblon mRNA with various intensities whereas the signals in astrocytes and oligodendrocytes were modest or negligible. Intense mRNA signals were(More)