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 À/À ) 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 À/À 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 À/À 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. Cell Death and Differentiation (2007) Eukaryotic mRNA synthesis by RNA polymerase II (pol II) is regulated by the concerted action of a set of transcription factors that control the activity of pol II during the initiation and elongation stages of transcription. At least six general transcription factors have been identified in eukaryotic cells and found to promote the selective binding of pol II to promoters and to support the basal level of transcription. 1 In addition, a diverse collection of elongation factors that promote efficient elongation of transcripts by pol II in vitro have also been identified. 2-4 These factors fall into two broad functional classes based on their ability to either reactivate arrested pol II or suppress the transient pausing of pol II. The first class is composed of members of the SII family. 3,5 The second class comprises a collection of elongation factors, including TFIIF, 6 Elongin, 7,8 ELL 9 and CSB, 10 which increase the overall rate of mRNA chain elongation by decreasing the frequency and/or duration of transient pausing of pol II at sites along the DNA template.Elongin was identified as a heterotrimer composed of A, B and C subunits of B770, 118 and 112 amino acids, respectively. 7,8,11,12 Elongin A is the transcriptionally active subunit, whereas Elongins B and C are positive regulatory subunits that can form an isolable Elongin BC subcomplex. 8,13,14 Although the functions of Elongin A in vivo remain largely unclear, Gerber et al. 15 have recently reported that the Drosophila homolog of Elongin A (dEloA) colocalizes with pol II at sites of active transcription on polytene chromosomes, and it also plays a critical role in heat shock gene expression in vivo. 15,16 Moreover, by the RNA interference (...

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