Budhram-Mahadeo V S, Irshad S, Bowen S, Lee S A, Samady L, Tonini G P, Latchman D S
Medical Molecular Biology Unit, Institute of Child Health, University College London, London, UK.
Oncogene. 2008 Jan 3;27(1):145-54. doi: 10.1038/sj.onc.1210621. Epub 2007 Jul 16.
Brn-3b transcription factor enhances proliferation of neuroblastoma (NB) and breast cancer cell lines in vitro and increases the rate and size of in vivo tumour growth, whereas reducing Brn-3b slows growth, both in vitro and in vivo. Brn-3b is elevated in >65% of breast cancer biopsies, and here we demonstrate that Brn-3b is also elevated in NB tumours. We show a significant correlation between Brn-3b and cyclin D1 (CD1) in breast cancers and NB tumours and cell lines. Brn-3b directly transactivates the CD1 promoter in co-transfection experiments, whereas electrophoretic mobility shift assay and chromatin immunoprecipitation assays demonstrate that Brn-3b protein binds to an octamer sequence located in the proximal CD1 promoter. Site-directed mutagenesis of this sequence resulted in loss of transactivation of the CD1 promoter by Brn-3b. Thus, Brn-3b may act to alter growth properties of breast cancer and NB cells by enhancing CD1 expression in these cells.
Brn-3b转录因子在体外可增强神经母细胞瘤（NB）和乳腺癌细胞系的增殖，并提高体内肿瘤生长的速率和大小，而降低Brn-3b水平则会减缓体外和体内的生长。在超过65%的乳腺癌活检样本中，Brn-3b水平升高，并且我们在此证明Brn-3b在NB肿瘤中也升高。我们显示在乳腺癌、NB肿瘤及细胞系中，Brn-3b与细胞周期蛋白D1（CD1）之间存在显著相关性。在共转染实验中，Brn-3b直接反式激活CD1启动子，而电泳迁移率变动分析和染色质免疫沉淀分析表明，Brn-3b蛋白与位于近端CD1启动子的一个八聚体序列结合。对该序列进行定点诱变导致Brn-3b对CD1启动子的反式激活丧失。因此，Brn-3b可能通过增强这些细胞中CD1的表达来改变乳腺癌和NB细胞的生长特性。
