Kuo Ping-Chang, Tsao Yeou-Ping, Chang Hung-Wei, Chen Po-Han, Huang Chu-Wei, Lin Shinn-Tsuen, Weng Yu-Tzu, Tsai Tzung-Chieh, Shieh Sheau-Yann, Chen Show-Li
Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Cancer Res. 2009 Dec 1;69(23):8877-85. doi: 10.1158/0008-5472.CAN-09-2023. Epub 2009 Nov 10.
Breast cancer amplified sequence 2 (BCAS2) was reported previously as a transcriptional coactivator of estrogen receptor. Here, we report that BCAS2 directly interacts with p53 to reduce p53 transcriptional activity by mildly but consistently decreasing p53 protein in the absence of DNA damage. However, in the presence of DNA damage, BCAS2 prominently reduces p53 protein and provides protection against chemotherapeutic agent such as doxorubicin. Deprivation of BCAS2 induces apoptosis in p53 wild-type cells but causes G(2)-M arrest in p53-null or p53 mutant cells. There are at least two apoptosis mechanisms induced by silencing BCAS2 in wild-type p53-containing cells. Firstly, it increases p53 retention in nucleus that triggers the expression of apoptosis-related genes. Secondly, it increases p53 transcriptional activity by raising p53 phosphorylation at Ser(46) and decreases p53 protein degradation by reducing p53 phosphorylation at Ser(315). We show for the first time that BCAS2, a small nuclear protein (26 kDa), is a novel negative regulator of p53 and hence a potential molecular target for cancer therapy.
乳腺癌扩增序列2（BCAS2）先前被报道为雌激素受体的转录共激活因子。在此，我们报告BCAS2在无DNA损伤时直接与p53相互作用，通过适度但持续降低p53蛋白来降低p53转录活性。然而，在存在DNA损伤的情况下，BCAS2显著降低p53蛋白，并对阿霉素等化疗药物提供保护作用。缺失BCAS2会诱导p53野生型细胞凋亡，但在p53缺失或p53突变细胞中导致G2-M期阻滞。在含野生型p53的细胞中，沉默BCAS2至少会诱导两种凋亡机制。首先，它增加p53在细胞核中的滞留，从而触发凋亡相关基因的表达。其次，它通过提高p53在Ser(46)位点的磷酸化增加p53转录活性，并通过降低p53在Ser(315)位点的磷酸化减少p53蛋白降解。我们首次表明，作为一种小核蛋白（26 kDa）的BCAS2是p53的新型负调节因子，因此是癌症治疗的潜在分子靶点。
