SPEN
小结
SPEN是抑癌基因，编码蛋白是SMRT/HDAC1相关的阻遏蛋白（SHARP），主要通过调节Notch，TCF/LEF，和EGFR信号通路来参与转录抑制和胚胎发生和发育。SHARP通过其相应的结构域直接与SMRT，HDAC1，和HDAC2结合。SPEN也通过结合类固醇受体RNA辅激活子SRA作为雌激素诱导型辅因子，这增强ERα活性并最终调节ERα靶基因的转录。研究发现，SPEN的突变和LOH导致的低表达可能是预测他莫昔芬反应的生物标志物。ERα阳性的乳腺癌细胞系表达更高水平SPEN与接受他莫昔芬辅助治疗的患者取得较好疗效的结果相关。
The SPEN gene encodes the protein, SMRT/HDAC1-associated repressor protein (SHARP), mainly involved in transcriptional repression, embryogenesis and development through regulation of the Notch, TCF/LEF, and EGFR signaling pathways. SHARP is a large 402 kDA protein composed of four N-terminal RNA-binding domains and a conserved C-terminal Spen Paralog and Ortholog C-terminal (SPOC) domain. Through these domains, SHARP directly interacts with SMRT, HDAC1, and HDAC2. SPEN also acts as an estrogen-inducible cofactor by binding the steroid receptor RNA coactivator SRA which enhances ERα activity and ultimately modulates the transcription of ERα target genes. Recent studies studying ERα-expressing breast cancer cell lines have identified mutations and LOH in SPEN that lead to underexpression that may be a predictive biomarker of tamoxifen response. ERα-positive breast cell lines expressing higher levels of SPEN correlated with better outcome in patients who received adjuvant tamoxifen therapy.