Related Experiment Video

Updated: Jun 23, 2026

Yeast As a Chassis for Developing Functional Assays to Study Human P53
14:57

Yeast As a Chassis for Developing Functional Assays to Study Human P53

Published on: August 4, 2019

Mdm2-mediated NEDD8 conjugation of p53 inhibits its transcriptional activity

Dimitris P Xirodimas1, Mark K Saville, Jean-Christophe Bourdon

  • 1University of Dundee, Ninewells Hospital and Medical School, Department of Surgery and Molecular Oncology, Dundee DD1 9SY, UK.

Cell
|July 10, 2004
PubMed

Insights

The Mdm2 E3 ligase modifies the p53 tumor suppressor with NEDD8, inhibiting its transcriptional activity. This reveals Mdm2

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Ubiquitin Biology

Background:

  • The NEDD8 conjugation pathway primarily regulates SCF ubiquitin ligase complexes.
  • The E3 ligase Mdm2 is known for its role in p53 ubiquitination and degradation.
  • The function of NEDD8 modification on non-SCF substrates remains largely unexplored.

Purpose of the Study:

  • To investigate the role of Mdm2 in NEDD8 conjugation.
  • To determine the effect of Mdm2-mediated NEDD8 modification on p53 activity.
  • To explore Mdm2's involvement in both ubiquitin and NEDD8 conjugation pathways.

Main Methods:

  • Utilized a temperature-sensitive NEDD8 conjugation mutant cell line (TS-41).
  • Employed a p53 mutant resistant to NEDDylation (3NKR).
  • Assessed Mdm2-dependent NEDD8 modification of p53 and its impact on transcriptional activity.

Main Results:

  • Demonstrated that Mdm2 mediates NEDD8 modification of the p53 tumor suppressor.
  • Showed that Mdm2 itself undergoes NEDD8 modification.
  • Confirmed that Mdm2-dependent NEDDylation of p53 inhibits its transcriptional activity.

Conclusions:

  • Mdm2 functions as an E3 ligase in both ubiquitin and NEDD8 conjugation pathways.
  • NEDD8 modification of p53 by Mdm2 serves as a regulatory mechanism controlling p53 function.
  • This expands the known roles of E3 ligases in substrate protein regulation.

More Related Videos

Continuous Fluorescence-Based Endonuclease-Coupled DNA Methylation Assay to Screen for DNA Methyltransferase Inhibitors06:07

Continuous Fluorescence-Based Endonuclease-Coupled DNA Methylation Assay to Screen for DNA Methyltransferase Inhibitors

Published on: August 5, 2022

Purification of Ubiquitinated p53 Proteins from Mammalian Cells10:55

Purification of Ubiquitinated p53 Proteins from Mammalian Cells

Published on: March 21, 2022

Related Concept Videos

Negative Regulator Molecules01:23

Negative Regulator Molecules

Positive regulators allow a cell to advance through cell cycle checkpoints. Negative regulators have an equally important role as they terminate a cell’s progression through the cell cycle—or pause it—until the cell meets specific criteria.
DNA Damage can Stall the Cell Cycle02:36

DNA Damage can Stall the Cell Cycle

In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
Master Transcription Regulators02:23

Master Transcription Regulators

Master transcription regulators are regulatory proteins that are predominantly responsible for regulating the expression of multiple genes. Often these genes work in concert to drive a  complex process. Activation of a master transcription regulator can lead to a cascade of transcriptional activation necessary for that outcome. These regulators can directly bind to the regulatory sequences of the various genes involved, or they can indirectly regulate transcription by binding to regulatory...
Inhibition of Cdk Activity02:34

Inhibition of Cdk Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the daughter...
DNA Damage Can Stall the Cell Cycle02:36

DNA Damage Can Stall the Cell Cycle

In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...