Polyubiquitination of p53 by a Ubiquitin Ligase Activity of p300

  title={Polyubiquitination of p53 by a Ubiquitin Ligase Activity of p300},
  author={Steven R. Grossman and Maria Divina E Deato and Chrystelle Brignone and Ho Man Chan and Andrew L. Kung and Hideaki Tagami and Yoshihiro Nakatani and David M Livingston},
  pages={342 - 344}
Rapid turnover of the tumor suppressor protein p53 requires the MDM2 ubiquitin ligase, and both interact with p300–CREB-binding protein transcriptional coactivator proteins. p53 is stabilized by the binding of p300 to the oncoprotein E1A, suggesting that p300 regulates p53 degradation. Purified p300 exhibited intrinsic ubiquitin ligase activity that was inhibited by E1A. In vitro, p300 with MDM2 catalyzed p53 polyubiquitination, whereas MDM2 catalyzed p53 monoubiquitination. E1A expression… 

Mono- Versus Polyubiquitination: Differential Control of p53 Fate by Mdm2

It is shown that low levels of Mdm2 activity induce monoubiquitination and nuclear export of p53, whereas high levels promote p53's polyubiquitinated and nuclear degradation.

OTUD5 Regulates p53 Stability by Deubiquitinating p53

As a novel deubiquitinating enzyme for p53, OTUD5 is required for the stabilization and the activation of a p53 response.

UBE4B, a ubiquitin chain assembly factor, is required for MDM2-mediated p53 polyubiquitination and degradation

It is proposed that inhibition of MDM2 binding to UBE4B may provide another approach to inhibitMDM2 E3 ligase activity for tumor suppressor p53, which could lead to novel anticancer therapies, with the possibility of reducing the public health burden from cancer.

The Chaperone-associated Ubiquitin Ligase CHIP Is Able to Target p53 for Proteasomal Degradation*

It is shown that the chaperone-associated ubiquitin ligase CHIP is able to induce the proteasomal degradation of p53, and that mutant and wild-type p53 transiently associate with molecular chaperones and can be diverted onto a degradation pathway through this association.

CBP and p300 are cytoplasmic E4 polyubiquitin ligases for p53

Analysis of p300 or CBP-deficient cells revealed that both coactivators were required for endogenous p53 polyubiquitination and the normally rapid turnover of p53 in unstressed cells, and surprisingly, p300/CBP ubiquitin ligase activities were absent in nuclear extracts and exclusively cytoplasmic.

p53 Ubiquitination and proteasomal degradation.

An in vitro degradation assay in which ubiquitinated p53 is incubated with purified 26S proteasomes can be used to provide insight into the biochemical nature of p53 ubiquitination and degradation.

The MDM2-p53 interaction.

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.

Cul4A Physically Associates with MDM2 and Participates in the Proteolysis of p53

Evidence is provided for a role of Cul4A in the MDM2-mediated proteolysis of p53 and for its role in the decay-rate and accumulation in response to DNA damage.

Regulation of the p53 tumor suppressor protein by Clycogen Synthase Kinase 3

It is concluded that GSK 3 regulates p53 levels by phosphorylating key sites in the central domain of the Mdm2 protein, which reveals a new mechanism for DNA damage-induced p53 accumulation and describes a post-ubiquitylation function of the H2O2 oncoprotein, the interaction of the mdm2protein with the proteasome.



Human mdm2 Mediates Multiple Mono-ubiquitination of p53 by a Mechanism Requiring Enzyme Isomerization*

It is shown that the multistep cascade of mdm2-mediated p53 ubiquitination can be reduced to three purified recombinant proteins: ubiquitin-conjugated E2, mDM2, and p53, and it is found that p53 is modified with multiple mono-ubiquitin moieties as opposed to a poly-ubsin chain.

Mdm2 Mutant Defective in Binding p300 Promotes Ubiquitination but Not Degradation of p53*

Genetic evidence is provided that p300 plays a pivotal role in the regulation of Mdm2-mediated p53 turnover by integrating the cellular ubiquitination and proteolytic processes.

Multiple C-Terminal Lysine Residues Target p53 for Ubiquitin-Proteasome-Mediated Degradation

It is suggested that p53 C-terminal lysine residues are the main sites of ubiquitin ligation, which target p53 for proteasome-mediated degradation.

In vivo ubiquitination and proteasome-mediated degradation of p53(1).

In this study, inhibitors of the 26S proteasome have been used to further explore the role of ubiquitin proteolysis in regulating p53 turnover and indicate that ubiquitIn-p53 conjugates were detected in untreated as well as gamma-irradiated cells, indicating that Ubiquitin-dependent proteolytic plays a role in the normal turnover of p53.

p300/CBP/p53 interaction and regulation of the p53 response.

Through physical interaction with p53, p300/CBP can both positively and negatively regulate p53 transactivation, as well as p53 protein turnover depending on cellular context and environmental stimuli, such as DNA damage.

Mdm2 promotes the rapid degradation of p53

It is proposed that the Mdm2-promoted degradation of p53 provides a new mechanism to ensure effective termination of the p53 signal.

Regulation of p53 stability by Mdm2

It is shown that interaction with Mdm2 can also result in a large reduction in p53 protein levels through enhanced proteasome-dependent degradation, which may contribute to the maintenance of low p53 concentrations in normal cells.

MDM2–HDAC1‐mediated deacetylation of p53 is required for its degradation

The results suggest that one major function of p53 acetylation is to promote p53 stability by preventingMDM2‐dependent ubiquitylation, while recruitment of HDAC1 by MDM2 promotes p53 degradation by removing these acetyl groups.

p300 binding by E1A cosegregates with p53 induction but is dispensable for apoptosis

E1A expression during infection of human cells may trigger redundant p53-independent and -dependent apoptotic pathways, implying that p53 induction may be linked to apoptosis induction by E1A.

Accumulation of p53 induced by the adenovirus E1A protein requires regions involved in the stimulation of DNA synthesis

It was found that in human HeLa cells and rodent cells, complex formation with p300 but not pRB was required for the rise in p53 levels, but in other human cell lines, E1A proteins which were able to form complexes with either p300 or pRB induced a significant increase in p 53 levels.