Cbl and human myeloid neoplasms: the Cbl oncogene comes of age.
Cbl and human myeloid neoplasms: the Cbl oncogene comes of age.
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DOI：
10.1158/0008-5472.can-10-0610
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发表时间：
2010-06-15
期刊：
影响因子：
11.2
通讯作者：
Lipkowitz S
中科院分区：
文献类型：
--
作者：
Kales SC;Ryan PE;Nau MM;Lipkowitz S
Cbl最初于1989年被发现，是v-Cbl癌基因的细胞同源物，而v-Cbl癌基因是引起小鼠骨髓性白血病和淋巴瘤的casns -1小鼠逆转录病毒的转化基因。Cbl是环指泛素连接酶家族的成员，该家族负向调节酪氨酸激酶的信号传导，并作为接头蛋白积极调节信号传导。直到过去两年，几乎没有证据表明Cbl蛋白与人类恶性肿瘤有关。最近的出版物已经证明了人髓系肿瘤中Cbl的纯合突变。虽然体外和动物转化模型表明Cbl突变形式作为癌基因，但细胞作用表明该蛋白可以作为肿瘤抑制基因。最近的数据开始调和这一矛盾，因为泛素连接酶功能（肿瘤抑制功能）的丧失与正信号功能（癌基因功能）的维持相耦合。这些数据也提供了潜在的治疗方法，骨髓疾病窝藏Cbl突变的见解。
Cbl was originally discovered in 1989 as the cellular homologue of the v-Cbl oncogene, the transforming gene of the Cas NS-1 murine retrovirus which causes myeloid leukemia and lymphomas in mice. Cbl is a member of a family of RING finger ubiquitin ligases which negatively regulate signaling by tyrosine kinases and which function as adaptor proteins to regulate signaling positively. Until the past two years, there was little evidence that Cbl proteins were involved in human malignancies. Recent publications have demonstrated homozygous mutations in Cbl in human myeloid neoplasms. While in vitro and animal transformation models suggested that mutant forms of Cbl acted as an oncogene, the cellular role suggested that the protein could serve as a tumor suppressor gene. The recent data begin to reconcile this paradox as the loss of ubiquitin ligase function (the tumor suppressor function) is coupled to the maintenance of the positive signaling function (the oncogene function). These data also provide insight into potential therapeutic approaches to myeloid disorders harboring Cbl mutations.