AIFsh, a novel apoptosis-inducing factor (AIF) pro-apoptotic isoform with potential pathological relevance in human cancer
AIFsh, a novel apoptosis-inducing factor (AIF) pro-apoptotic isoform with potential pathological relevance in human cancer
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DOI：
10.1074/jbc.m509884200
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发表时间：
2006-03-10
影响因子：
4.8
通讯作者：
Susin, SA
中科院分区：
文献类型：
--
作者：
Delettre, C;Yuste, VJ;Susin, SA
AIF是caspase非依赖性细胞死亡的主要介导者。在人类和小鼠中，它分别由位于X染色体Q25-26和A6区域的单个基因编码。先前的研究证实，AIF编码AIF和AIF-exB两种亚型的蛋白质。在这里，我们确定了第三种AIF亚型，它是由位于AIF内含子9的另一个转录起始点引起的。由此产生的mRNA编码与AIF的C-末端结构域(氨基酸353-613)相对应的胞浆蛋白。我们将这个新的亚型命名为AIFShort(AIFsh)。在HeLa细胞中过表达AIFsh可导致核转位和caspase非依赖性细胞死亡。一旦进入细胞核，AIFsh就会引起与AIF相同的效应，即染色质凝聚和大规模(50kb)DNA片段化。相反，AIF抑制蛋白Hsp70并不能排除这些促凋亡作用。这些发现证明AIFsh是AIF的一种新的促凋亡异构体，也揭示了AIF的第一个N末端352个氨基酸不是其凋亡活性所必需的。此外，我们还证明了AIFsh在来自肾、外阴、皮肤、甲状腺和胰腺的肿瘤细胞中显著下调，而伽玛射线治疗则引起AIFsh上调。总体而言，我们的结果确定了AIF依赖途径的一个新成员，并为caspase非依赖性细胞死亡在肿瘤形成/抑制中的作用提供了新的线索。
AIF is a main mediator of caspase-independent cell death. It is encoded by a single gene located on chromosome X, region q25 - 26 and A6 in humans and mice, respectively. Previous studies established that AIF codes for two isoforms of the protein, AIF and AIF-exB. Here, we identify a third AIF isoform resulting from an alternate transcriptional start site located at intron 9 of AIF. The resulting mRNA encodes a cytosolic protein that corresponds to the C-terminal domain of AIF ( amino acids 353 - 613). We named this new isoform AIFshort (AIFsh). AIFsh overexpression in HeLa cells results in nuclear translocation and caspase-independent cell death. Once in the nucleus, AIFsh provokes the same effects than AIF, namely chromatin condensation and large scale ( 50 kb) DNA fragmentation. In contrast, these apoptogenic effects are not precluded by the AIF-inhibiting protein Hsp70. These findings identify AIFsh as a new pro-apoptotic isoform of AIF, and also reveal that the first N-terminal 352 amino acids of AIF are not required for its apoptotic activity. In addition, we demonstrate that AIFsh is strongly down-regulated in tumor cells derived from kidney, vulva, skin, thyroid, and pancreas, whereas, gamma-irradiation treatment provokes AIFsh up-regulation. Overall, our results identify a novel member of the AIF-dependent pathway and shed new light on the role of caspase-independent cell death in tumor formation/suppression.