Pratilas Christine A, Taylor Barry S, Ye Qing, Viale Agnes, Sander Chris, Solit David B, Rosen Neal
Department of Pediatrics, Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Proc Natl Acad Sci U S A. 2009 Mar 17;106(11):4519-24. doi: 10.1073/pnas.0900780106. Epub 2009 Feb 27.
Tumors with mutant BRAF and those with receptor tyrosine kinase (RTK) activation have similar levels of phosphorylated ERK, but only the former depend on ERK signaling for proliferation. The mitogen-activated protein kinase, extracellular signal-regulated kinase kinase (MEK)/ERK-dependent transcriptional output was defined as the genes whose expression changes significantly 8 h after MEK inhibition. In (V600E)BRAF cells, this output is comprised of 52 genes, including transcription factors that regulate transformation and members of the dual specificity phosphatase and Sprouty gene families, feedback inhibitors of ERK signaling. No such genes were identified in RTK tumor cells, suggesting that ERK pathway signaling output is selectively activated in BRAF mutant tumors. We find that RAF signaling is feedback down-regulated in RTK cells, but is insensitive to this feedback in BRAF mutant tumors. Physiologic feedback inhibition of RAF/MEK signaling down-regulates ERK output in RTK cells; evasion of this feedback in mutant BRAF cells is associated with increased transcriptional output and MEK/ERK-dependent transformation.
具有BRAF突变的肿瘤和那些具有受体酪氨酸激酶（RTK）激活的肿瘤具有相似水平的磷酸化ERK，但只有前者的增殖依赖于ERK信号传导。丝裂原活化蛋白激酶、细胞外信号调节激酶激酶（MEK）/ERK依赖性转录输出被定义为在MEK抑制后8小时其表达发生显著变化的基因。在（V600E）BRAF细胞中，这种输出由52个基因组成，包括调节转化的转录因子以及双特异性磷酸酶和Sprouty基因家族的成员，它们是ERK信号传导的反馈抑制剂。在RTK肿瘤细胞中未鉴定出此类基因，这表明ERK途径信号传导输出在BRAF突变肿瘤中被选择性激活。我们发现RAF信号传导在RTK细胞中被反馈下调，但在BRAF突变肿瘤中对这种反馈不敏感。RAF/MEK信号传导的生理性反馈抑制会下调RTK细胞中的ERK输出；BRAF突变细胞中这种反馈的逃避与转录输出增加和MEK/ERK依赖性转化有关。
