Inhibitor of apoptosis-stimulating protein of p53 (iASPP) prevents senescence and is required for epithelial stratification
Inhibitor of apoptosis-stimulating protein of p53 (iASPP) prevents senescence and is required for epithelial stratification
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DOI：
10.1073/pnas.1102292108
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发表时间：
2011-10-04
影响因子：
11.1
通讯作者：
Lu, Xin
中科院分区：
文献类型：
--
作者：
Notari, Mario;Hu, Ying;Lu, Xin
p53的促凋亡蛋白抑制剂（Inhibitor of aptosis-stimulating protein of p53，iASPP）是ASPP家族中最古老的成员，是一种进化上保守的p53抑制剂。iASPP也是p65 RelA的结合伴侣和负调节剂。由于p65 RelA和p53家族成员在控制细胞命运方面通常具有相反的作用，因此了解iASPP可以调节其活性的细胞背景是很重要的。为了解决这个问题，并在体内研究iASPP的生物学意义，我们产生了一个转基因小鼠，其中iASPP的表达是由Cre/loxP重组系统控制。我们观察到iASPP能够防止小鼠胚胎成纤维细胞的过早细胞衰老。iASPP损失导致体外和体内原代角质形成细胞的分化增加。在复层上皮中，核iASPP通常与基底角质形成细胞的核中的p63共定位。与此一致，iASPP结合p63并在体外抑制TAp 63 a和Δ Np 63 α的转录活性，并在体内影响p63调节基因如兜甲蛋白和外皮蛋白的表达水平。与此相反，在相同条件下，p65 RelA经常表达为细胞质蛋白在基底层上的复层上皮细胞，很少与核iASPP共定位。因此，iASPP可能通过调节p63的转录活性而不是p65 RelA来控制上皮分层。这项研究确定了iASPP作为衰老的抑制剂和控制上皮分层的关键因素。
Inhibitor of apoptosis-stimulating protein of p53 (iASPP) is the most ancient member of the ASPP family of proteins and an evolutionarily conserved inhibitor of p53. iASPP is also a binding partner and negative regulator of p65RelA. Because p65RelA and the p53 family members often have opposite effects in controlling cell fate, it is important to understand the cellular context in which iASPP can regulate their activities. To address this question and to study the biological importance of iASPP in vivo, we generated a transgenic mouse in which iASPP expression is controlled by the Cre/loxP recombination system. We observed that iASPP is able to prevent premature cellular senescence in mouse embryonic fibroblasts. iASPP loss resulted in increased differentiation of primary keratinocytes both in vitro and in vivo. In stratified epithelia, nuclear iASPP often colocalized with p63 in the nuclei of basal keratinocytes. Consistent with this, iASPP bound p63 and inhibited the transcriptional activity of both TAp63a and Delta Np63 alpha in vitro and influenced the expression level of p63-regulated genes such as loricrin and involucrin in vivo. In contrast, under the same conditions, p65RelA was frequently expressed as a cytoplasmic protein in the suprabasal layers of stratified epithelia and rarely colocalized with nuclear iASPP. Thus, iASPP is likely to control epithelial stratification by regulating p63's transcriptional activity, rather than p65RelA's. This study identifies iASPP as an inhibitor of senescence and a key player in controlling epithelial stratification.