iASPP oncoprotein is a key inhibitor of p53 conserved from worm to human
iASPP oncoprotein is a key inhibitor of p53 conserved from worm to human
复制标题
DOI：
10.1038/ng1070
复制
发表时间：
2003-02-01
期刊：
影响因子：
30.8
通讯作者：
Lu, X
中科院分区：
文献类型：
--
作者：
Bergamaschi, D;Samuels, Y;Lu, X
我们以前已经表明，ASPP 1和ASPP 2是p53的特异性激活剂;野生型p53在人类乳腺癌中耐受的一种机制是通过ASPP活性的丧失。我们进一步证明了53 BP 2，对应于ASPP 2的C-末端片段，作为p53的显性负性抑制剂（参考文献1）。因此，类似于53 BP 2的ASPP的抑制形式可以允许细胞绕过p53和ASPP蛋白的肿瘤抑制功能。在这里，我们描述了这样一种蛋白质，iASPP（ASPP家族的抑制性成员），由PPP 1 R13 L在人类和猿-1线虫编码。iASPP是一种进化上保守的p53抑制剂;在线虫或人类细胞中分别通过RNA介导的干扰或反义RNA抑制iASPP，诱导p53依赖性细胞凋亡。此外，iASPP是一种癌蛋白，与Ras、E1 A和E7协同作用，但不与突变型p53协同作用，在体外转化细胞。iASPP的表达增加也赋予对紫外线辐射和顺铂诱导的细胞凋亡的抗性。在表达野生型p53和正常水平ASPP的人乳腺癌中，iASPP表达上调。抑制iASPP可以为治疗表达野生型p53的肿瘤提供重要的新策略。
We have previously shown that ASPP1 and ASPP2 are specific activators of p53; one mechanism by which wild-type p53 is tolerated in human breast carcinomas is through loss of ASPP activity. We have further shown that 53BP2, which corresponds to a C-terminal fragment of ASPP2, acts as a dominant negative inhibitor of p53 (ref. 1). Hence, an inhibitory form of ASPP resembling 53BP2 could allow cells to bypass the tumor-suppressor functions of p53 and the ASPP proteins. Here, we characterize such a protein, iASPP (inhibitory member of the ASPP family), encoded by PPP1R13L in humans and ape-1 in Caenorhabditis elegans. iASPP is an evolutionarily conserved inhibitor of p53; inhibition of iASPP by RNA-mediated interference or antisense RNA in C elegans or human cells, respectively, induces p53-dependent apoptosis. Moreover, iASPP is an oncoprotein that cooperates with Ras, E1A and E7, but not mutant p53, to transform cells in vitro. Increased expression of iASPP also confers resistance to ultraviolet radiation and to cisplatin-induced apoptosis. iASPP expression is upregulated in human breast carcinomas expressing wild-type p53 and normal levels of ASPP. Inhibition of iASPP could provide an important new strategy for treating tumors expressing wild-type p53.