FAM83B mediates EGFR- and RAS-driven oncogenic transformation
FAM83B mediates EGFR- and RAS-driven oncogenic transformation
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DOI：
10.1172/jci60517
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发表时间：
2012-09-01
影响因子：
15.9
通讯作者：
Jackson, Mark W.
中科院分区：
文献类型：
--
作者：
Cipriano, Rocky;Graham, James;Jackson, Mark W.
生长信号传导的异常调节是癌症发展的标志，其通常通过生长因子受体或其下游效应物的组成性激活而发生。利用基于验证的插入突变（VBIM）技术，我们鉴定了具有序列相似性的家族83，成员B（FAM 83 B），基于其在永生化人乳腺上皮细胞（HMEC）转化中取代RAS的能力。我们发现FAM 83 B与RAS的下游效应物CRAF共沉淀。FAM 83 B与CRAF的结合破坏了CRAF/14-3-3相互作用并增加了CRAF膜定位，导致MAPK和哺乳动物雷帕霉素靶蛋白（mTOR）信号传导升高。FAM 83 B的消融抑制了肿瘤衍生细胞或RAS转化的HMEC的增殖和恶性表型，暗示FAM 83 B是EGFR/RAS/MAPK信号传导的关键中介。对人类肿瘤标本的分析显示，FAM 83 B表达在癌症中显著升高，并与特定癌症亚型、肿瘤分级增加和总生存率降低相关。累积起来，这些结果表明FAM 83 B是一种致癌基因，并可能代表治疗干预的新靶点。
Aberrant regulation of growth signaling is a hallmark of cancer development that often occurs through the constitutive activation of growth factor receptors or their downstream effectors. Using validation-based insertional mutagenesis (VBIM), we identified family with sequence similarity 83, member B (FAM83B), based on its ability to substitute for RAS in the transformation of immortalized human mammary epithelial cells (HMECs). We found that FAM83B coprecipitated with a downstream effector of RAS, CRAF. Binding of FAM83B with CRAF disrupted CRAF/14-3-3 interactions and increased CRAF membrane localization, resulting in elevated MAPK and mammalian target of rapamycin (mTOR) signaling. Ablation of FAM83B inhibited the proliferation and malignant phenotype of tumor-derived cells or RAS-transformed HMECs, implicating FAM83B as a key intermediary in EGFR/RAS/MAPK signaling. Analysis of human tumor specimens revealed that FAM83B expression was significantly elevated in cancer and was associated with specific cancer subtypes, increased tumor grade, and decreased overall survival. Cumulatively, these results suggest that FAM83B is an oncogene and potentially represents a new target for therapeutic intervention.