Identification of STAG1 as a key mediator of a p53-dependent apoptotic pathway
Identification of STAG1 as a key mediator of a p53-dependent apoptotic pathway
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DOI：
10.1038/sj.onc.1207270
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发表时间：
2004-10-07
期刊：
影响因子：
8
通讯作者：
Nakamura, Y
中科院分区：
文献类型：
--
作者：
Anazawa, Y;Arakawa, H;Nakamura, Y
突变型p53（p53- 121 F），其中苯丙氨酸取代第121位丝氨酸残基，可以诱导细胞凋亡比野生型p53（wt-p53）更有效。鉴于这一观察结果，我们认为，一个或多个乳腺癌相关的p53靶基因可能优先诱导的p53- 121 F。我们进行了cDNA微阵列分析，以确定这样的基因，使用从LS 174 T结肠癌细胞感染的腺病毒载体含有p53- 121 F（Ad-p53- 121 F）或wt-p53（Ad-p53）的mRNA。STAG 1基因是在用Ad-p53- 121 F感染的细胞中显示出比Ad-wtp 53感染的细胞更高表达水平的转录物之一。编码的产物似乎含有一个跨膜结构域，以及SH 3和WW的结合基序。在另外两个癌细胞系中，STAG 1 mRNA的表达以p53依赖的方式响应于各种遗传毒性应激而被诱导;此外，STAG 1的强制表达导致了另外几个癌细胞系的凋亡。使用RNA干扰方法抑制内源性STAG 1降低了细胞凋亡反应，无论是由Ad-p53- 121 F还是Ad-p53诱导的。这些结果表明，STAG 1，一个新的转录靶点p53，介导p53依赖性细胞凋亡，并可能是一个很好的候选人，为下一代基因治疗。
A mutant version of p53 (p53-121F), in which phenylalanine replaces the 121st serine residue, can induce apoptosis more effectively than wild-type p53 (wt-p53). In view of this observation, we considered that one or more apoptosis-related p53-target genes might be preferentially induced by p53-121F. We carried out cDNA microarray analysis to identify such genes, using mRNAs isolated from LS174T colon-cancer cells infected by adenovirus vectors containing either p53-121F(Ad-p53-121F) or wt-p53 (Ad-p53). The STAG1 gene was one of the transcripts showing higher expression levels in cells infected with Ad-p53-121F as opposed to Ad-wtp53. The encoded product appears to contain a transmembrane domain, and binding motifs for SH3 and WW. In two other cancer cell lines, the expression of STAG1 mRNA was induced in response to various genotoxic stresses in a p53-dependent manner; moreover, enforced expression of STAG1 led to apoptosis in several additional cancer cell lines. Suppression of endogenous STAG1 using the RNA-interference method reduced the apoptotic response, whether induced by Ad-p53-121F or Ad- p53. These results suggest that STAG1, a novel transcriptional target for p53, mediates p53-dependent apoptosis, and might be a good candidate for next-generation gene therapy.