p53 mRNA controls p53 activity by managing Mdm2 functions

  title={p53 mRNA controls p53 activity by managing Mdm2 functions},
  author={Marco Marques Candeias and Laurence Malbert-Colas and Darren J. Powell and Chrysoula Daskalogianni and Magdalena M. Maslon and Nadia Naski and Karima Bourougaa and Fabien Calvo and Robin F{\aa}hraeus},
  journal={Nature Cell Biology},
The E3 ubiquitin ligase Mdm2 is a focal regulator of p53 tumour suppressor activity. It binds p53, promoting its polyubiquitination and degradation, and also controls p53 synthesis. However, it is not known how this dual function of Mdm2 on p53 synthesis and degradation is achieved. Here we show that the p53 mRNA region encoding the Mdm2-binding site interacts directly with the RING domain of Mdm2. This impairs the E3 ligase activity of Mdm2 and promotes p53 mRNA translation. We also show that… 

The p53 mRNA-Mdm2 interaction

How the new insights into the regulation of p53 expression levels can help to shed light on the origin of this elegant feedback system and on the function of Mdm2 isoforms is discussed.

p53 mRNA and p53 Protein Structures Have Evolved Independently to Interact with MDM2.

The results indicate that the temperature-regulated p53 mRNA-MDM2 interaction evolved to become kinase regulated in the mammalian DNA damage response and suggest that the negative regulation of p53 by MDM2 via protein-protein interaction evolved in vertebrates following changes in the BOX-I flanking sequence.

The regulation of p53 synthesis.

The regulation of p53 synthesis and its implications for controlling p53 activity under normal conditions and during different types of stress response are discussed.

Modulation of p53 binding to MDM2: computational studies reveal important roles of Tyr100

Molecular dynamics simulations have revealed how the binding of p53 toMDM2 is modulated by the conformational mobility of Y100 which is the gatekeeper residue in MDM2.

Dual function of MDM2 and MDMX toward the tumor suppressors p53 and RB

Findings that suggest that the MDM2 and MDMX proteins have a dual function on both p53 and RB are contextualized.

Mdm2 and MdmX as Regulators of Gene Expression.

increasing evidence suggests that Mdm2 and MdmX affect p53 target gene specificity and influence the activity of other transcription factors, and MDM2 itself may even function as a transcription co-factor through post-translational modification of chromatin.

p53 and little brother p53/47: linking IRES activities with protein functions

It is discussed here in detail how diverse cellular stress pathways trigger alterations in the cap-dependent and cap-independent translation of p53 mRNA and how changes in the relative expression levels of p 53 isoforms result in more differentiated p53 activity.

MDM2’s dual mRNA binding domains co-ordinate its oncogenic and tumour suppressor activities

The data illustrate how twoMDM2 domains selectively bind specific mRNAs in response to cellular conditions to promote, or suppress, cell growth and how p14Arf coordinates MDM2’s activity towards p53 and E2F1.



p53 stability and activity is regulated by Mdm2-mediated induction of alternative p53 translation products

It is demonstrated that Mdm2 induces translation of the p53 mRNA from two alternative initiation sites, giving full-length p53 and another protein with a relative molecular mass of approximately 47K; this protein is designated as p53/47, which stabilizes p53 in the presence of MDM2, and alters the expression levels of p53-induced gene products.

Wild type p53 can mediate sequence-specific transactivation of an internal promoter within the mdm2 gene.

It is suggested that p53 can induce transcription from an internal promoter located within the mdm2 gene, which raises the possibility that, in addition to increasing the overall levels of mdm1 mRNA, wt p53 may also modulate the repertoire of mDM2 transcripts present within the cell.

Serine 15 phosphorylation stimulates p53 transactivation but does not directly influence interaction with HDM2

Biochemical data indicate that the mechanism by which phosphorylation of Ser15 stimulates p53‐dependent transactivation occurs through increased binding to the p300 coactivator protein, and indicate that Ser15‐dependent regulation of transactivation is independent of any involvement in modulating MDM2 binding.

SUMO‐1 modification activates the transcriptional response of p53

It is shown that p53 is modified by the small ubiquitin‐like protein SUMO‐1 at a single site, K386, in the C‐terminus of the protein, and may represent a novel target for the development of therapeutically useful modulators of the p53 response.

Expression of p53 and p53/47 are controlled by alternative mechanisms of messenger RNA translation initiation

It is shown that cap-dependent and cap-independent mechanisms of initiation govern the translation of the p53 mRNA, and that some cytotoxic drugs require the presence of full-length p53 to induce apoptosis, whereas for others p53/47 is sufficient.

Structure of the MDM2 Oncoprotein Bound to the p53 Tumor Suppressor Transactivation Domain

The crystal structure of the 109-residue amino-terminal domain of MDM2 bound to a 15-Residue transactivation domain peptide of p53 revealed that MDM 2 has a deep hydrophobic cleft on which the p53 peptide binds as an amphipathic α helix, supporting the hypothesis thatMDM2 inactivates p53 by concealing its transactivationdomain.

Phosphorylation of p53 on Key Serines Is Dispensable for Transcriptional Activation and Apoptosis*♦

Investigation of the role of p53 phosphorylation on six key serine residues for p53 activation using nutlin-3, a recently developed small molecule MDM2 antagonist shows that it is not required for activation of p 53 target genes or biological responses in vivo.

The MDM2 Oncoprotein Binds Specifically to RNA through its RING Finger Domain

Observations, showing that MDM2 binds the L5/5S ribosomal ribonucleoprotein particle and can also bind to specific RNA sequences or structures, suggest a role forMDM2 in translational regulation in a cell.

Human MDM2 Isoforms Translated Differentially on Constitutive versus p53-Regulated Transcripts Have Distinct Functions in the p53/MDM2 and TSG101/MDM2 Feedback Control Loops

It is reported here that human p75MDM2 is an N-terminally truncated mixture of protein isoforms produced by the initiation of translation at two distinct internal AUG codons, and the mechanism of formation of the principal MDM2 isoforms is revealed, as well as the differential effects of p53 on the production of these isoforms.

Identification of a Novel p53 Functional Domain That Is Necessary for Mediating Apoptosis*

Deletion of the N-terminal 23 amino acids compromises, but does not abolish, p53 induction of apoptosis, and it is postulate that the apoptotic activity in p53(Gln22-Ser23) and p53 (Δ1–42) is still transcription-dependent.