Dominant effects of Δ40p53 on p53 function and melanoma cell fate.
Dominant effects of Δ40p53 on p53 function and melanoma cell fate.
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α40p53 对 p53 功能和黑色素瘤细胞命运的显着影响。
DOI：
10.1038/jid.2013.391
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Scrable,HeidiJ
中科院分区：
文献类型：
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作者：
Takahashi,Rie;Markovic,SvetomirN;Scrable,HeidiJ
TP 53基因编码12种不同的亚型，其中一些可以改变p53活性的基因组改变的情况下。内源性p53亚型已被确定在癌症中，然而，这些亚型的功能仍然不清楚。在黑色素瘤中，TP 53突变的频率相对于其他癌症较低，这表明这些异构体在调节TP 53活性方面可能具有更大的作用。我们假设p53功能和细胞命运可能会因Δ 40 p53的存在而改变，Δ 40 p53是一种胚胎同种型，缺失全长蛋白质的前40个N-末端氨基酸，包括反式激活和Mdm 2结合结构域。为了验证这一假设，我们用编码Δ 40 p53的慢病毒转导肿瘤和正常细胞。我们发现，外源性Δ 40 p53在癌细胞和非癌细胞中引起细胞凋亡并增加内源性活化p53的水平，这导致显著水平的细胞死亡，特别是在癌细胞中。激活的p53分子与Δ 40 p53形成核异源四聚体，并改变下游p53转录靶水平，包括具有死亡结构域的p53诱导蛋白和细胞周期蛋白依赖性激酶抑制剂p21。Δ 40 p53改变了这些下游p53靶基因的启动子占据率，使细胞命运转向凋亡，远离细胞周期停滞。我们表明，p53的肿瘤抑制可以通过依赖于其与Δ 40 p53相互作用的替代途径发生。
TheTP53gene encodes 12 distinct isoforms, some of which can alter p53 activity in the absence of genomic alteration. Endogenous p53 isoforms have been identified in cancers; however, the function of these isoforms remains unclear. In melanoma, the frequency ofTP53mutations is relatively low compared with other cancers, suggesting that these isoforms may have a larger role in regulatingTP53activity. We hypothesized that p53 function and therefore cell fate might be altered by the presence of Δ40p53, an embryonic isoform missing the first 40 N-terminal amino acids of the full-length protein including the transactivation and Mdm2-binding domains. To test this hypothesis, we transduced tumor and normal cells with a lentivirus encoding Δ40p53. We found that exogenous Δ40p53 caused apoptosis and increased the levels of endogenous, activated p53 in both cancerous and non-cancerous cells, which led to significant levels of cell death, particularly in cancer cells. Activated p53 molecules formed nuclear heterotetramers with Δ40p53 and altered downstream p53 transcription target levels including p53-induced protein with death domain and cyclin-dependent kinase inhibitor, p21. Δ40p53 altered the promoter occupancy of these downstream p53 target genes in such a way that it shifted cell fate toward apoptosis and away from cell cycle arrest. We show that tumor suppression by p53 can occur via an alternate route that relies on its interaction with Δ40p53.