Does MDM2 bind to p53?

The main regulator of p53 is the E3 ubiquitin ligase MDM2, which binds to p53’s transactivation domain and functions by both preventing p53’s transcriptional activity and targeting it for degradation.

How is MDM2 activated?

Mdm2 has been identified as a p53 interacting protein that represses p53 transcriptional activity. Mdm2 achieves this repression by binding to and blocking the N-terminal trans-activation domain of p53. Mdm2 is a p53 responsive gene—that is, its transcription can be activated by p53.

What happens if MDM2 is inhibited?

Inhibiting the MDM2-p53 interaction with an MDM2 antagonist leads to reactivation of p53 in cancers with wild-type or functional p53. The interaction between MDM2 and p53 forms an autoregulatory feedback loop [3, 9].

How does Mdm2 bind to the p53 transactivation domain?

MDM2 binding to the NH 2 terminal transactivation domain of p53 blocks its transcriptional activity directly ( 12, 30 ). More importantly, MDM2 functions as the E3 ligase that ubiquitinates p53 for proteasome degradation ( 14, 18 ).

What is the strength of the MDM2-p53 bond?

Experimental measurements of the strength of the p53-MDM2 bond range from a Kd of 60 to 700 n m, depending on the length of the p53 peptide ( 34 –37 ).

How does Mdm2 and p53 form a feedback loop?

Regulation of p53 by MDM2. p53 and MDM2 form an autoregulatory feedback loop. p53 stimulates the expression of MDM2; MDM2, in turn, inhibits p53 activity because it stimulates its degradation in the nucleus and the cytoplasm, blocks its transcriptional activity, and promotes its nuclear export.

Why are p53 proteins deficient 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 ).