Induction of apoptosis and cellular senescence in mice lacking transcription elongation factor, Elongin A
Induction of apoptosis and cellular senescence in mice lacking transcription elongation factor, Elongin A
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DOI：
10.1038/sj.cdd.4402067
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发表时间：
2007-04-01
影响因子：
12.4
通讯作者：
Aso, T.
中科院分区：
文献类型：
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作者：
Miyata, K.;Yasukawa, T.;Aso, T.
延伸蛋白A是一种转录延伸因子，可增加RNA聚合酶II导致的mRNA链延伸的总体速率。为了更深入地了解Elongin A的生理功能，我们产生了Elongin A缺陷小鼠。Elongin A纯合子突变体（Elongin A（-/-））胚胎表现出严重的发育迟缓，并在妊娠第10.5天至12.5天死亡，最有可能是由于广泛的细胞凋亡。此外，小鼠胚胎成纤维细胞（MEFs）衍生自Elongin A（-/）-胚胎不仅表现出增加的凋亡，但也衰老样的生长缺陷伴随着p38 MAPK和p53的激活。通过RNA干扰敲低MEFs中的延伸蛋白A也显著诱导衰老表型。一项使用p38 MAPK和p53抑制剂以及产生p53缺失背景的Elongin A缺陷小鼠的研究表明，p38 MAPK和p53途径都负责诱导衰老样表型，而其他信号传导途径似乎参与Elongin A（-/）-细胞凋亡的介导。总之，我们的研究结果表明，延伸蛋白A是必需的早期胚胎发育和下调其活性的基因转录与细胞衰老密切相关。
Elongin A is a transcription elongation factor that increases the overall rate of mRNA chain elongation by RNA polymerase II. To gain more insight into the physiological functions of Elongin A, we generated Elongin A-deficient mice. Elongin A homozygous mutant (Elongin A(-/-)) embryos demonstrated a severely retarded development and died at between days 10.5 and 12.5 of gestation, most likely due to extensive apoptosis. Moreover, mouse embryonic fibroblasts (MEFs) derived from Elongin A(-/)-embryos exhibited not only increased apoptosis but also senescence-like growth defects accompanied by the activation of p38 MAPK and p53. Knockdown of Elongin A in MEFs by RNA interference also dramatically induced the senescent phenotype. A study using inhibitors of p38 MAPK and p53 and the generation of Elongin A-deficient mice with p53-null background suggests that both the p38 MAPK and p53 pathways are responsible for the induction of senescence-like phenotypes, whereas additional signaling pathways appear to be involved in the mediation of apoptosis in Elongin A(-/)-cells. Taken together, our results suggest that Elongin A is required for the transcription of genes essential for early embryonic development and downregulation of its activity is tightly associated with cellular senescence.