Induction of apoptosis and cellular senescence in mice lacking transcription elongation factor, Elongin A.
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.
Miyata
K
K
Department of Functional Genomics, Kochi Medical School, Kohasu, Oko-cho, Nankoku, Kochi, Japan.
Yasukawa
T
T
Fukuda
M
M
Takeuchi
T
T
Yamazaki
K
K
Sakumi
K
K
Tamamori-Adachi
M
M
Ohnishi
Y
Y
Ohtsuki
Y
Y
Nakabeppu
Y
Y
Kitajima
S
S
Onishi
S
S
Aso
T
T
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D016922:Cellular Senescence / Q000235:genetics*; D000075065:Elongin; D005260:Female; D005313:Fetal Death / Q000235:genetics; D005333:Fetus / Q000002:abnormalities; D005347:Fibroblasts / Q000166:cytology; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011247:Pregnancy; D014157:Transcription Factors / Q000235:genetics*; D035602:Transcriptional Elongation Factors / Q000235:genetics* / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
C000616403:Eloa protein, mouse; D000075065:Elongin; D014157:Transcription Factors; D035602:Transcriptional Elongation Factors; D016159:Tumor Suppressor Protein p53; D048051:p38 Mitogen-Activated Protein Kinases