Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide.
Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide.
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DOI：
10.1038/leu.2012.119
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发表时间：
2012-11
期刊：
影响因子：
11.4
通讯作者：
Chopra, R.
中科院分区：
文献类型：
--
作者：
Lopez-Girona, A.;Mendy, D.;Ito, T.;Miller, K.;Gandhi, A. K.;Kang, J.;Karasawa, S.;Carmel, G.;Jackson, P.;Abbasian, M.;Mahmoudi, A.;Cathers, B.;Rychak, E.;Gaidarova, S.;Chen, R.;Schafer, P. H.;Handa, H.;Daniel, T. O.;Evans, J. F.;Chopra, R.
沙利度胺和免疫调节药物来那度胺在血液系统恶性肿瘤中具有治疗活性。普遍表达的E3连接酶蛋白小脑（CRBN）已被确定为沙利度胺的主要致畸靶点。我们的研究表明，沙利度胺、来那度胺和另一种免疫调节药物泊马度胺结合内源性CRBN和重组CRBN - dna损伤结合蛋白-1 （DDB1）复合物。CRBN介导来那度胺和泊马度胺在骨髓瘤细胞中的抗增殖活性，以及来那度胺和泊马度胺诱导的T细胞细胞因子的产生。来那度胺和波马度胺抑制了表达沙利度胺结合能力野生型CRBN的HEK293T细胞中CRBN的自富素化，但对沙利度胺结合缺陷型CRBNYW/AA不起作用。在KMS12骨髓瘤细胞中，CRBN野生型蛋白而非CRBNYW/AA突变蛋白的过表达，会放大波马度胺介导的c-myc和IRF4表达的降低以及p21WAF-1表达的增加。在H929骨髓瘤细胞系中，长期选择来那度胺耐药伴随着CRBN的减少，而在对泊马度胺和来那度胺均耐药的DF15R骨髓瘤细胞中，CRBN蛋白未检测到。我们的生物物理、生化和基因沉默研究表明，CRBN是来那度胺和泊马度胺的近似的、治疗上重要的分子靶点。
Thalidomide and the immunomodulatory drug, lenalidomide, are therapeutically active in hematological malignancies. The ubiquitously expressed E3 ligase protein cereblon (CRBN) has been identified as the primary teratogenic target of thalidomide. Our studies demonstrate that thalidomide, lenalidomide and another immunomodulatory drug, pomalidomide, bound endogenous CRBN and recombinant CRBN–DNA damage binding protein-1 (DDB1) complexes. CRBN mediated antiproliferative activities of lenalidomide and pomalidomide in myeloma cells, as well as lenalidomide- and pomalidomide-induced cytokine production in T cells. Lenalidomide and pomalidomide inhibited autoubiquitination of CRBN in HEK293T cells expressing thalidomide-binding competent wild-type CRBN, but not thalidomide-binding defective CRBNYW/AA. Overexpression of CRBN wild-type protein, but not CRBNYW/AA mutant protein, in KMS12 myeloma cells, amplified pomalidomide-mediated reductions in c-myc and IRF4 expression and increases in p21WAF-1 expression. Long-term selection for lenalidomide resistance in H929 myeloma cell lines was accompanied by a reduction in CRBN, while in DF15R myeloma cells resistant to both pomalidomide and lenalidomide, CRBN protein was undetectable. Our biophysical, biochemical and gene silencing studies show that CRBN is a proximate, therapeutically important molecular target of lenalidomide and pomalidomide.
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影响因子：
78.5
作者：
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通讯作者：
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