What does ubiquitination do to p53?
E4F1-mediated ubiquitination of p53 increases the fraction of protein associated with chromatin, and this association specifically coincides with p53-mediated transcriptional activation of genes involved with cell cycle arrest, but not apoptosis.
How is p53 regulated by MDM2?
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 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).
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.
Is Mdm2 a ubiquitin?
Mdm2 is an important negative regulator of the p53 tumor suppressor. Mdm2 protein functions both as an E3 ubiquitin ligase that recognizes the N-terminal trans-activation domain (TAD) of the p53 tumor suppressor and as an inhibitor of p53 transcriptional activation.
How is the binding of MDM2 to p53 inhibited?
Here we show that MDM2 inhibits p53 DNA binding activity in vitro and in vivo. MDM2 binding promotes p53 to adopt a mutant-like conformation, losing reactivity to antibody Pab1620, while exposing the Pab240 epitope. The acidic domain of MDM2 is required to induce p53 conformational change and inhibit p53 DNA binding.
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.
How p53 regulates the cell cycle?
P53 forms a homotetrameric transcription factor that is reported to directly regulate ~500 target genes, thereby controlling a broad range of cellular processes, including cell cycle arrest, cell senescence, DNA repair, metabolic adaptation and cell death.
What set of genes does p53 act as a transcription factor?
2.4. 2 p53. p53 functions as a transcription factor regulating downstream genes important in cell cycle arrest, DNA repair, and apoptosis. The p53 tumor suppressor continues to hold distinction as the most frequently mutated gene in human cancer.
Is MDM2 a tumor suppressor gene or a proto oncogene?
MDM2 is an oncogene that mainly functions to modulate p53 tumor suppressor activity. In normal cells the MDM2 protein binds to the p53 protein and maintains p53 at low levels by increasing its susceptibility to proteolysis by the 26S proteosome.