Regulation of HIF-1alpha stability by novel interacting proteins

  • 첨부된 파일이 없습니다.
  • Hit 105
  • Writer 이태화
  • 2014-01-15



Regulation of HIF-1alpha stability by novel interacting proteins.


- Date/Time : Fri October 11., 2002

          PM 14:00-16:00 

- Speaker : 김규원 교수

           - 서울대학교 약학대학


- Place : Chemistry Bldg. #401

- For inquires : Professor Sung Ho Ryu Dept. of Life Science

              생명과학과 류성호 교수 (☎279-2292)

- Abstract

    Hypoxia inducible factor-1 (HIF-1) is a master transcription factor that controls transcriptional activation of a number of genes responsive to the low cellular oxygen tension, including vascular endothelial growth factor (VEGF), erythropoietin, and glycolytic enzymes. The stability and activity of HIF-1a are regulated by binding to various proteins such as pVHL, p53 and p300/CBP. Recently, prolyl hydroxylation was identified as a key regulatory event that targets the HIF-1a subunit for proteasomal degradation via the pVHL ubiquitination complex.

    Our laboratory identified novel proteins such as ARD1, Jab1 to interact HIF-1a using the yeast two-hybrid screening. In this report, we reveal an important function for ARD1 in mammalian cells as a protein acetyltransferase by direct binding to HIF-1a to regulate its stability. We present further evidence showing that ARD1-mediated acetylation enhances interaction of HIF-1a with pVHL and HIF-1a ubiquitination, suggesting that the acetylation of HIF-1a by ARD1 is critical to proteasomal degradation. Therefore, we have concluded that the role of ADR1 in the acetylation of HIF-1a provides a key regulatory mechanism underlying HIF-1a stability.

    Moreover, Jab1 enhanced transcriptional activity of HIF-1 under hypoxia, led to increase the expression of VEGF, a major HIF-1 target gene. Furthermore, Jab1 increased HIF-1a protein levels, which was due to the enhanced HIF-1a stability. The binding of HIF-1a and p53 tumor suppressor protein, negative regulator of HIF-1a stability, was interfered in Jab1 dependent manner. Collectively, these results indicate that Jab1 should be considered as a novel regulator of HIF-1a stability via direct interaction.