| Project/Area Number |
17390082
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
General medical chemistry
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| Research Institution | Kochi University |
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Principal Investigator |
ASO Teijiro Kochi University, Faculty of Medicine, Professor (20291289)
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| Co-Investigator(Kenkyū-buntansha) |
SHUIN Taro Kochi University, Faculty of Medicine, Professor (80179019)
KITAJIMA Shigetaka Tokio Medical and Dental University, Medical Research instiitute, Professor (30186241)
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| Project Period (FY) |
2005 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥14,500,000 (Direct Cost: ¥13,600,000、Indirect Cost: ¥900,000)
Fiscal Year 2007: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Fiscal Year 2006: ¥4,100,000 (Direct Cost: ¥4,100,000)
Fiscal Year 2005: ¥6,500,000 (Direct Cost: ¥6,500,000)
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| Keywords | Elongin / transcription elongation / RNA nolvmerase II / Vcellular senescence / apoptosis / p53 / 938 MAPK / hypoxic response / Rpb1 / ubiquitin / ubiquitin ligase / DNA damage |
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| Research Abstract |
1. 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, while 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.
2. Functional characterization of a mammalian transcription factor, Elongin A
To further understand the function of Elongin A in vivo, we have carried out the structure-function analysis of Elongin A and identified sequences critical to its nuclear localization and direct interaction with pol II. Moreover, we have analyzed the replication fork movement in wild-type and Elongin A^<-/-> MEFs, and shown the possibility that the genomic instability observed in Elongin A^<-/-> MEFs might be caused by the replication fork collapse due to Elongin A deficiency.
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