A new mouse model to explore the initiation, progression, and therapy of BRAFV600E-induced lung tumors
A new mouse model to explore the initiation, progression, and therapy of BRAFV600E-induced lung tumors
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DOI：
10.1101/gad.1516407
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发表时间：
2007-02-15
影响因子：
10.5
通讯作者：
McMahon, Martin
中科院分区：
文献类型：
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作者：
Dankort, David;Filenova, Elena;McMahon, Martin
在大约 6% 的人类恶性肿瘤中检测到突变激活的 BRAF(V600E) (BRAF(VE))，并促进 MEK1/2-ERK1/2 通路持续激活。我们设计了 BRaf(CA) 小鼠，使其在 Cre 介导的重组之前表达正常 BRaf，之后 BRaf(VE) 在生理水平上表达。感染表达 Cre 重组酶的腺病毒的 BRafCA 小鼠会产生良性肺部肿瘤，很少进展为腺癌。此外，MEK1/2 的药理学抑制可预防 BRaf(VE) 诱导的肺肿瘤。 BRafVE 表达最初诱导增殖，随后出现具有某些衰老特征的生长停滞。与 Ink4a/Arf 和 TP53 肿瘤抑制功能一致，BRafVE 表达与任一基因座突变相结合导致癌症进展。
Mutationally activated BRAF(V600E) (BRAF(VE)) is detected in similar to 6% of human malignancies and promotes sustained MEK1/2-ERK1/2 pathway activation. We have designed BRaf(CA) mice to express normal BRaf prior to Cre-mediated recombination after which BRaf(VE) is expressed at physiological levels. BRafCA mice infected with an Adenovirus expressing Cre recombinase developed benign lung tumors that only rarely progressed to adenocarcinoma. Moreover, BRaf(VE)-induced lung tumors were prevented by pharmacological inhibition of MEK1/2. BRafVE expression initially induced proliferation that was followed by growth arrest bearing certain hallmarks of senescence. Consistent with Ink4a/Arf and TP53 tumor suppressor function, BRafVE expression combined with mutation of either locus led to cancer progression.