How does MDM2 control p53?
How does MDM2 control p53?
MDM2 negatively regulates p53 by targeting the ubiquitin ligase activity of MDM2. A complementary approach to prevent p53 degradation by MDM2 is to develop agents designed to inhibit the E3 ligase activity of MDM2 directly so as to mimic the effects of ARF or the ribosomal protein L11.
How does MDM2 regulate stability of p53?
Endogenous levels of Mdm2 are sufficient to regulate p53 stability, and overexpression of Mdm2 can reduce the amount of endogenous p53. Because mdm2 is transcriptionally activated by p53, this degradative pathway may contribute to the maintenance of low p53 concentrations in normal cells.
Does MDM2 phosphorylate p53?
MDM2-p53 binding has been extensively studied as a target of regulation by DNA damage. Several studies showed that DNA double-strand breaks induce phosphorylation of p53 S15 by ATM or DNA-PK. ATM also activates Chk2, which in turn phosphorylates p53 on S20, which is part of the MDM2-binding site.
What is the p53 pathway?
The p53 pathway is composed of a network of genes and their products that are targeted to respond to a variety of intrinsic and extrinsic stress signals that impact upon cellular homeostatic mechanisms that monitor DNA replication, chromosome segregation and cell division (Vogelstein et al., 2000).
How is p53 stabilized?
p53 is Stabilized by Different Stresses These post-translational modifications include phosphorylation, acetylation, methylation, ubiquitination and sumoylation and are observed at approximately 24 different sites. A variety of different stresses stabilize and activate p53.
What region of p53 does MDM2 bind?
Stress response by p53 is dependent on intricate mechanisms that regulate its level and activity. The MDM2/MDMX feedback loop plays a pivotal role in controlling the cellular level and transcriptional activity of p53 (8). MDM2 binds to the p53 NT to promote p53 ubiquitination and degradation in the absence of stress.
How is p53 regulated?
p53 is regulated by an array of posttranslational modifications both during normal homeostasis and in stress-induced responses. More than 36 different amino acids within p53 have been shown to be modified in various biochemical and cell culture studies (Figure 1) (Kruse and Gu, 2008b).
How is p53 activated?
The tumour suppressor protein p53 is stabilised and activated in response to ionising radiation. This is known to depend on the kinase ATM; recent results suggest ATM acts via the downstream kinase Chk2/hCds1, which stabilises p53 at least in part by direct phosphorylation of residue serine 20.
