Deregulated Intracellular Signaling by Mutated c-CBL in Myeloid Neoplasms
Deregulated Intracellular Signaling by Mutated c-CBL in Myeloid Neoplasms
复制标题
DOI：
10.1158/1078-0432.ccr-09-2341
复制
发表时间：
2010-08-01
影响因子：
11.5
通讯作者：
Sanada, Masashi
中科院分区：
文献类型：
--
作者：
Ogawa, Seishi;Shih, Lee-Yung;Sanada, Masashi
c-CBL编码一种120 kda的蛋白，在多种细胞类型中参与细胞内信号转导。最近，c-CBL的频繁突变在骨髓肿瘤中被报道，显示出骨髓增生异常和骨髓增生的特征，其中大多数突变以纯合子状态存在，这是11q等位基因转换的结果。c-CBL对多种酪氨酸激酶具有泛素E3连接酶活性，从而负调控酪氨酸激酶信号传导。因此，c-CBL似乎具有肿瘤抑制功能，其缺失促进肿瘤发生。另一方面，一旦发生突变，它就会转化为一种致癌蛋白，并通过一种功能增益导致异常的信号转导而导致髓性白血病的发生。抑制突变的CBL蛋白或其激活的信号通路将在CBL突变的髓系肿瘤治疗中发挥作用。临床癌症研究；16 (15);3825 - 31所示。(c) 2010年aacr。
c-CBL encodes a 120-kDa protein involved in intracellular signal transduction in a wide variety of cell types. Recently, frequent mutations of c-CBL have been reported in myeloid neoplasms showing both myelodysplastic and myeloproliferative features, in which most mutations are present in a homozygous state, as a result of allelic conversion in 11q. c-CBL has ubiquitin E3 ligase activity for a wide variety of tyrosine kinases, and thereby, negatively regulates tyrosine kinase signaling. Accordingly, c-CBL seems to have tumor suppressor functions, loss of which promotes tumorigenesis. On the other hand, once mutated, it is converted to an oncogenic protein and commits to myeloid leukemogenesis through a kind of gain of function causing aberrant signal transduction. The inhibition of mutant CBL protein or signaling pathways that it activates would have a role in therapeutics of myeloid neoplasms with CBL mutations. Clin Cancer Res; 16(15); 3825-31. (C) 2010 AACR.