Does MDM2 phosphorylate p53?
Principally, MDM2 is an E3 ligase and promotes p53 degradation through a ubiquitin-dependent pathway on nuclear and cytoplasmic 26S proteasomes (14, 17–20).
Does MDM2 ubiquitination p53?
Mdm2 is a key repressor of p53. It is an E3 ligase that promotes p53 ubiquitination and proteasomal degradation. In addition, binding of Mdm2 to p53 can directly inhibit the transcriptional activity of p53 through a number of mechanisms. Mdm2 is ubiquitinated and is degraded by the proteasome.
What does mutant p53 do?
The TP53 gene provides instructions for making a protein called tumor protein p53 (or p53). This protein acts as a tumor suppressor, which means that it regulates cell division by keeping cells from growing and dividing (proliferating) too fast or in an uncontrolled way.
Is MDM2 a tumor suppressor gene or a proto oncogene?
MDM2 is an oncogene that mainly functions to modulate p53 tumor suppressor activity.
What region of p53 does MDM2 bind?
N-terminal domain
The primary p53 binding site on mdm2 is located in its N-terminal domain. Through binding to p53 at its N-terminal transactivation domain, mdm2 directly blocks the transcriptional activation function of p53.
What does ubiquitination of p53 do?
The ubiquitination pathway is a highly dynamic and coordinated process that regulates degradation as well as numerous processes of proteins within a cell. The p53 tumor suppressor and several factors in the pathway are regulated by ubiquitin as well as ubiquitin-like proteins.
Does MDM2 cause apoptosis?
Our data indicate that in the absence of mdm2 fibroblasts can induce apoptosis, suggesting that cell type specificity may be due to the levels of mdm2 expressed.
Does mutant p53 interfere with the intramolecular mechanism of Mdm2?
The results suggest that mutant p53 interferes with the intramolecular autoactivation mechanism of MDM2, contributing to reduced ubiquitination and increased accumulation in tumor cells. Keywords: E3 ligase; MDM2; RING domain; acidic domain; conformation; mutant p53; ubiquitination.
How does the p53-Mdm2 complex differ from wild-type p53?
Here, we show that in the mutant p53-MDM2 complex, the mutant p53 core domain binds to the MDM2 acidic domain with significantly higher avidity than wild-type p53. The mutant p53-MDM2 complex is deficient in catalyzing ubiquitin release from the activated E2 conjugating enzyme.
Why are mutant p53 proteins stable in tumor cells?
By the same token, mutant p53 proteins in tumor cells are stable because they are deficient in transactivating MDM2—hence they have a defective negative feedback loop (reviewed e.g. in 16 ). Principally, MDM2 is an E3 ligase and promotes p53 degradation through a ubiquitin-dependent pathway on nuclear and cytoplasmic 26S proteasomes ( 14, 17 –20 ).
Why is the p53-Mdm2 interaction important for cancer therapy?
Because the p53-MDM2 interaction is structurally and biologically well understood, the design of small lipophilic molecules that disrupt or prevent it has become an important target for cancer therapy.