Mdm2-mediated NEDD8 conjugation of p53 inhibits its transcriptional activity (Cell, 2004, 118:83-97)

報告日期: 2006/04/11
報告時間: 15:10/16:00
報告學生: 陳琮明
講評老師: 張 玲
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Mdm2-Mediated NEDD8 Conjugation of p53 Inhibits Its Transcriptional Activity

Cell 118, 83-97 (2004)

Time: 2006/04/11 15:10~16:00           Place: Room 602

Speaker: 基醫所博二 陳琮明           Commentator:張玲老師

Abstract:

        Neural precursor cell expressed developmentally downregulated 8 (NEDD8) is the member of ubiquitin-like family and highly conserved across species.  NEDD8 share 60% amino acid sequence identity to ubiquitin (Ub) and can be used as a covalent modifier of proteins with similar mechanism of ubiquitination.  Genetic studies in plant, animal, and fungal system have highlighted the importance of the NEDD8 conjugation pathway in cell proliferation, viability, and development.  At the molecular level, the only well- characterized substrate for NEDD8 conjugation (neddylation) is members of the cullin family.  Cullins are common subunits of SCF complexes, which regulate the stability of various proteins involved in cell cycle control and signal transduction, including p27, IkBa, and HIF1-a.  There are also substantial evidence suggesting an intimate link between NEDD8-activated proteolysis and tumorigenesis.  The p53 is a well-studied tumor suppressor protein with a short life due to Ub-medicated proteasomal degradation.  Mdm2 is a key regulator of the stability of p53 by promoting the conjugation of Ub.  Biochemical studies showed that Mdm2 can act as an E3 Ub ligase by its C terminal RING finger domain.  Mdm2 can also regulate its own stability through an autoubiquitination activity and targeting itself for proteasomal degradation.  In this study, the author showed a novel neddylation pathway that involved in the regulation of p53 and mdm2.  Mdm2 can promote NEDD8 modification of the p53 protein and inhibits its transcriptional activity.  Mdm2 is also modified with NEDD8 itself with similar characteristics of autoubiquitination.  These finding provide that mdm2 is an E3 ligase of NEDD8 conjugation pathway and may function as a dual regulator of substrate protein by either ubiquitination or neddylation.

Reference:

1.      Harper, J.W. Neddylating the guardian: Mdm2 catalyzed conjugation of Nedd8 to p53. Cell 118, 2-4 (2004).

2.      Mani, A. and Gelmann, E.P. The ubiquitin-proteasome pathway and its role in cancer. J. Clin. Oncol. 21, 4776-89 (2005). 

3.      Pan, Z.Q. et al. Nedd8 on cullin: building an expressway to protein destruction. Oncogene 23, 1986-97 (2004).