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Differential role of ARD1 in the regulation of HIF-1a and p53 stability
Reports NRF is supported by Research Projects( Differential role of ARD1 in the regulation of HIF-1a and p53 stability | 2004 Year | 김세희(서울대학교) ) data is submitted to the NRF Project Results
Researcher who has been awarded a research grant by Humanities and Social Studies Support Program of NRF has to submit an end product within 6 months(* depend on the form of business)
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Project Number E00013
Year(selected) 2004 Year
the present condition of Project 종료
State of proposition 재단승인
Completion Date 2007년 01월 19일
Year type 결과보고
Year(final report) 2007년
Research Summary
  • Korean
  • ARD1은 인간과 쥐 세포에서 여러 종류의 isoform들을 가지고 있으며, 이들은 세포내에서 서로 다른 기능을 가질 것으로 보인다. 특히, ARD1 variant들 중, 암세포의 혈관신생에 중요한 전사 인자인 HIF-1alpha 단백질의 안정성에 직접적으로 관여하는 것이 mARD1225으로, HIF-1a 에 의해 유도되는 혈관신생 과정에서 mARD1225의 항암활성에 대한 가능성을 높여주고 있다. 또한, mARD1에 의한 HIF-1a 아세틸화 현상이 HDAC1과 3에 의해 가역적으로 조절되었다. 이러한 가역적이 반응이 HIF-1a의 안정성에 기여하는 여러 조절 단백질들 (pVHL, Mdm2, HSP90)과의 결합에 관여하여, HIF-1a의 안정성을 조절하는 것으로 관찰되었다. 더불어, mARD1는 세포 내 스트레스에 민감하게 발현되는 p53 단백질의 안정성을 증가시키는데, 이것은 HIF-1a 단백질의 안정성 조절과 반대되는 현상으로, p53과 Mdm2와의 결함을 억제시킴으로써, p53의 안정성을 높이는 것으로 보였다.
    결론적으로, 본 연구에서는 mARD1가 HIF-1a 와 p53 단백질들의 안정성을 다르게 조절함으로써, 암세포에서 HIF-1a 단백질에 의해 유도되는 혈관신생과정이나 혹은 p53의 활성이 증가하는 세포 내 스트레스 반응과 같은 과정에 중요한 조절 단백질로 작용할 것으로 생각된다. 따라서, 앞으로 mARD1에 관련된 표적 단백질들을 스크리닝 하는 연구를 병행함으로써, mARD1의 기전을 밝혀 나가는 것과 ARD1의 isoform들을 통한 다양한 기능 연구가 더욱더 필요할 것으로 보인다.
  • English
  • ARD1 has several isoforms in mammalian cell lines, and their roles differ with respect to HIF-1a stability and acetylation. Among ARD1 isofroms, mARD1225 (mARD1) degrades HIF-1a protein via promoting HIF-1a acetylation. In addition, HDAC1 and 3 directly interact with ODD domain of HIF-1a and block mARD1-mediated inhibition of HIF-1a by decreasing its acetylation, and stabilize HIF-1a protein via cotrolling the interactions with its regulators such as pVHL, Mdm2, and HSP90. Furthermore, it showed that the role of mARD1 as a regulator of p53 from the results that mARD1 directly interacts with p53 protein and decreases the binding between p53 and Mdm2, leading to stabilization of p53 under hypoxia.
    In summary, mARD1 differentially regulates HIF-1a and p53 stability via controlling the interactions with their regulators which are involved in their degradation. Moreover, these results are important in understanding the mechanism for the modulation of HIF-1a stability in a prolonged hypoxia, and proposed that mARD1 may be a critical target protein in the biological processes including angiogenesis, cell damage, and apoptosis.
Research result report
  • Abstract
  • Arrest-defective-1 (ARD1) was first identified in Saccharomyces cerevisiae and has N-terminal acetyltransferase activity. Previously, it was reported that mouse ARD1 (mARD1) degrades HIF-1a protein via its acetylation. In this study, it was found that ARD1 has several isoforms in mammalian cell lines, and ARD1 variants have different functions. In addition, it seems likely that mARD1 may differently involved in the regulation of HIF-1a and p53 stabiltiy. Therefore, to evaluate these observations, it was performed as following; 1) identification of ARD1 variants in mammalian cells and their effects in the regulation of HIF-1a stability and acetylation, 2) regulatory mechanism of HIF-1a protein via its reversible acetylation in prolonged hypoxia and 3) role of mARD1 in the regulation of p53 stability.
  • Research result and Utilization method
  • mARD1 differentially regulates HIF-1a and p53 stability via controlling the interactions with their regulators which are involved in their degradation. Moreover, these results are important in understanding the mechanism for the modulation of HIF-1a stability in a prolonged hypoxia, and proposed that mARD1 may be a critical target protein in the biological processes including angiogenesis, cell damage, and apoptosis.
  • Index terms
  • HIF-1alpha, ARD1, acetylation, deacetylation, HDAC
  • List of digital content of this reports
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