Centre Georges-François Leclerc, Molecular Genetics Laboratory, Dijon, France.
Oncogene. 2010 Apr 29;29(17):2577-84. doi: 10.1038/onc.2009.525. Epub 2010 Jan 25.
Expression of survivin, a member of the inhibitor of apoptosis protein family, is elevated in human cancers and considered as a new therapeutic target. Mechanism upregulating survivin expression in tumour cells is poorly understood. In this study, we show that breast cancer patients harbouring a polymorphism G235A in the survivin promoter present a higher level of survivin expression. This polymorphism creates a binding site for the transcription factor GATA-1 inducing a second GATA-1-binding site in survivin promoter. At the mRNA level, GATA-1 was present in breast carcinomas and adjacent normal tissues, whereas the protein was only detected in carcinomas by western blot and immunohistochemistry. Transfection of wild-type and different constitutively active GATA-1 mutants (serine 26, 178 or 310) showed that only phospho-serine 26 GATA-1 was able to increase survivin expression. This increase was higher in G235A than in G235G cell lines. Phospho-serine 26 GATA-1 bound directly survivin promoter, with a stronger interaction in G235A than in G235G polymorphism indicating that both GATA-1-binding sites are functional. These data identify GATA-1 as a key feature in tumour aggressiveness by enhancing survivin expression and delineate its targeting as a possible new therapeutic strategy in breast carcinomas.
生存素（survivin）是凋亡抑制蛋白家族的一员，其在人类癌症中的表达升高，被认为是一个新的治疗靶点。肿瘤细胞中生存素表达上调的机制尚未完全阐明。在本研究中，我们发现乳腺癌患者中生存素启动子的 G235A 多态性与更高水平的生存素表达相关。该多态性创造了一个转录因子 GATA-1 的结合位点，在生存素启动子中诱导第二个 GATA-1 结合位点。在 mRNA 水平，GATA-1 存在于乳腺癌及相邻正常组织中，而 Western blot 和免疫组织化学仅在癌组织中检测到该蛋白。转染野生型和不同组成型激活的 GATA-1 突变体（丝氨酸 26、178 或 310）表明，只有磷酸化丝氨酸 26 GATA-1 能够增加生存素的表达。在 G235A 细胞系中，这种增加高于 G235G 细胞系。磷酸化丝氨酸 26 GATA-1 直接结合生存素启动子，在 G235A 中的结合更强，表明两个 GATA-1 结合位点均具有功能。这些数据表明，GATA-1 通过增强生存素的表达成为肿瘤侵袭性的关键特征，并描绘了其作为乳腺癌潜在治疗策略的靶向作用。
