Goodall Jane, Martinozzi Silvia, Dexter Timothy J, Champeval Delphine, Carreira Suzanne, Larue Lionel, Goding Colin R
Signaling and Development Laboratory, Marie Curie Research Institute, The Chart, Oxted, Surrey RH8 0TL, United Kingdom.
Mol Cell Biol. 2004 Apr;24(7):2915-22. doi: 10.1128/MCB.24.7.2915-2922.2004.
Constitutive activation of the Wnt/beta-catenin signaling pathway is a notable feature of a large minority of cases of malignant melanoma, an aggressive and increasingly common cancer. The identification of target genes downstream from this pathway is therefore crucial to our understanding of the disease. The POU domain transcription factor Brn-2 has been implicated in control of proliferation and melanoma survival, and its expression is strongly upregulated in melanoma. We show here that in vivo Brn-2 is expressed in melanocytes but not in embryonic day 11.5 melanoblasts and that its expression is directly controlled by the Wnt/beta-catenin signaling pathway in melanoma cell lines and in transgenic mice. Moreover, silent interfering RNA-mediated inhibition of Brn-2 expression in melanoma cells overexpressing beta-catenin results in significantly decreased proliferation. These results, together with the observation that BRAF signaling also induces Brn-2 expression, reveal that Brn-2 is a focus for the convergence of two key melanoma-associated signaling pathways that are linked to cell proliferation.
Wnt/β-连环蛋白信号通路的组成性激活是大多数恶性黑色素瘤病例的一个显著特征，恶性黑色素瘤是一种侵袭性且日益常见的癌症。因此，识别该信号通路下游的靶基因对于我们理解这种疾病至关重要。POU结构域转录因子Brn-2与黑色素瘤的增殖控制和存活有关，并且其在黑色素瘤中表达强烈上调。我们在此表明，在体内，Brn-2在黑素细胞中表达，但在胚胎第11.5天的成黑素细胞中不表达，并且其表达在黑色素瘤细胞系和转基因小鼠中直接受Wnt/β-连环蛋白信号通路控制。此外，在过表达β-连环蛋白的黑色素瘤细胞中，沉默干扰RNA介导的Brn-2表达抑制导致增殖显著降低。这些结果，连同BRAF信号也诱导Brn-2表达这一观察结果，揭示Brn-2是与细胞增殖相关的两条关键黑色素瘤相关信号通路汇聚的焦点。
