β-Catenin induces immortalization of melanocytes by suppressing p16INK4a expression and cooperates with N-Ras in melanoma development
β-Catenin induces immortalization of melanocytes by suppressing p16INK4a expression and cooperates with N-Ras in melanoma development
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DOI：
10.1101/gad.450107
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发表时间：
2007-11-15
影响因子：
10.5
通讯作者：
Larue, Lionel
中科院分区：
文献类型：
--
作者：
Delmas, Veronique;Beermann, Friedrich;Larue, Lionel
肿瘤进展是一个多步骤的过程，其中促增殖突变必须伴有衰老抑制。在黑色素瘤中，NRAS和BRAF的激活突变提供促增殖信号，而p16(Ink4a)基因失活则绕过衰老过程。黑色素瘤还经常表现出Wnt/β -连环蛋白通路的组成性激活，据推测这会诱导增殖，就像在癌中一样。我们在此表明，与预期相反，稳定的β -连环蛋白减少了体内黑素母细胞的数量，并通过沉默p16Ink4a启动子使原代皮肤黑素细胞永生化。重要的是，在一种新的黑色素瘤小鼠模型中，稳定的β -连环蛋白绕过了对p16Ink4a突变的需求，并且与激活的N - Ras癌基因一起，导致黑色素瘤具有高外显率和短潜伏期。结果显示，Wnt和丝裂原活化蛋白（MAP）激酶通路之间的协同作用可能代表了支撑黑色素瘤发生的一种重要机制，黑色素瘤是一种极具侵袭性且日益常见的疾病。
Tumor progression is a multistep process in which proproliferation mutations must be accompanied by suppression of senescence. In melanoma, proproliferative signals are provided by activating mutations in NRAS and BRAF, whereas senescence is bypassed by inactivation of the p16(Ink4a) gene. Melanomas also frequently exhibit constitutive activation of the Wnt/beta-catenin pathway that is presumed to induce proliferation, as it does in carcinomas. We show here that, contrary to expectations, stabilized beta-catenin reduces the number of melanoblasts in vivo and immortalizes primary skin melanocytes by silencing the p16Ink4a promoter. Significantly, in a novel mouse model for melanoma, stabilized beta-catenin bypasses the requirement for p16Ink4a mutations and, together with an activated N-Ras oncogene, leads to melanoma with high penetrance and short latency. The results reveal that synergy between the Wnt and mitogen-activated protein (MAP) kinase pathways may represent an important mechanism underpinning the genesis of melanoma, a highly aggressive and increasingly common disease.