Inhibition of presenilin 1 expression is promoted by p53 and p21WAF-1 and results in apoptosis and tumor suppression
Inhibition of presenilin 1 expression is promoted by p53 and p21WAF-1 and results in apoptosis and tumor suppression
复制标题
DOI：
10.1038/nm0798-835
复制
发表时间：
1998-07-01
期刊：
影响因子：
82.9
通讯作者：
Telerman, A
中科院分区：
文献类型：
--
作者：
Roperch, JP;Alvaro, V;Telerman, A
之前，我们克隆了一个 cDNA 片段 TSIP 2（肿瘤抑制因子抑制途径克隆 2），通过 M1-LTR6 细胞的 Northern 印迹分析检测到 p53 诱导的细胞凋亡过程中 3 kb mRNA 下调 (1)。克隆全长 TSIP 2 cDNA 表明它对应于早老素 1 (PS1) 基因，据报道该基因在早发家族性阿尔茨海默病中发生突变(2-4)。在这里，我们证明 PS1 在一系列 p53 依赖性和 p53 依赖性细胞凋亡和肿瘤抑制模型系统中下调。为了研究这种下调的生物学相关性，我们用反义 PS1 cDNA 稳定转染 U937 细胞。这些 U937 转染子中 PS1 的下调导致生长减少，细胞凋亡比例增加。当注射到患有严重联合免疫缺陷病的纯合小鼠（scid/scid小鼠）中时，这些细胞显示出对其恶性表型的抑制。我们的结果表明，最初在神经退行性疾病中发现的 PS1 也可能参与癌症相关途径的调节。
Previously, we cloned a cDNA fragment, TSIP 2 (tumor suppressor inhibited pathway clone 2), that detects by northern blot analysis of M1-LTR6 cells a 3-kb mRNA downregulated during p53-induced apoptosis(1). Cloning the full-length TSIP 2 cDNA showed that it corresponds to the presenilin 1 (PS1) gene, in which mutations have been reported in early-onset familial Alzheimer's disease(2-4). Here we demonstrate that PS1 is downregulated in a series of model systems for p53-dependent and p53-independent apoptosis and tumor suppression. To investigate the biological relevance of this downregulation, we stably transfected U937 cells with antisense PS1 cDNA. The downregulation of PS1 in these U937 transfectants results in reduced growth with an increased fraction of the cells in apoptosis. When injected into mice homozygous for severe combined immunodeficiency disease (scid/scid mice), these cells show a suppression of their malignant phenotype. Our results indicate that PS1, initially identified in a neurodegenerative disease, may also be involved in the regulation of cancer-related pathways.