Induction of apoptosis and cellular senescence in mice lacking transcription elongation factor, Elongin A

K. Miyata, T. Yasukawa, M. Fukuda, T. Takeuchi, K. Yamazaki, K. Sakumi, M. Tamamori-Adachi, Y. Ohnishi, Y. Ohtsuki, Y. Nakabeppu, S. Kitajima, S. Onishi, T. Aso

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Abstract

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-I-) 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-I- 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-I- 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.

Original languageEnglish
Pages (from-to)716-726
Number of pages11
JournalCell Death and Differentiation
Volume14
Issue number4
DOIs
Publication statusPublished - Apr 1 2007

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All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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