1. ¹Department of Functional Genomics, Kochi Medical School, Kohasu, Oko-cho, Nankoku, Kochi, Japan
2. ²Department of Gastroenterology and Hepatology, Kochi Medical School, Kohasu, Oko-cho, Nankoku, Kochi, Japan
3. ³Department of Biochemical Genetics, Medical Research Institute, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo, Japan
4. ⁴Department of Tumor Pathology, Kochi Medical School, Kohasu, Oko-cho, Nankoku, Kochi, Japan
5. ⁵Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Maidashi, Higashi-ku, Fukuoka, Japan
6. ⁶Microbial Chemistry Research Foundation, Kamiosaki, Shinagawa-ku, Tokyo, Japan

Correspondence: T Aso, Department of Functional Genomics, Kochi Medical School, Kohasu, Oko-cho, Nankoku, Kochi 783-8505, Japan. Tel: +81 88 880 2279; Fax: 81 88 880 2281; E-mail: asot@med.kochi-u.ac.jp

⁷These authors contributed equally to this work.

Received 19 May 2006; Revised 4 October 2006; Accepted 23 October 2006; Published online 15 December 2006.

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^-/-) 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.