The molecular dynamics of MDM2

Nicholson, Judith; Hupp, Ted R.

doi:10.4161/cc.9.10.11597

Cited by 19 publications

(16 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…2. This is consistent with recent data showing that small linear and intrinsically unstructured peptide motifs, such as those in the C terminus of p53, can interact with a target protein through distinct and specific amino acid side chain contacts (41). Thus, this Ser 269 site on p53 can be solvent-exposed, is in dynamic equilibrium, and is a potential phosphoacceptor site that could have pleotropic effects on p53 folding and function.…”

Section: In Vitro Kinase Screens Identify a Novel Phosphoacceptor Sitsupporting

confidence: 91%

A Novel p53 Phosphorylation Site within the MDM2 Ubiquitination Signal

Fraser

Vojtěšek

Hupp

2010

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Exposure to a wide variety of genotoxic and metabolic stresses leads to the activation of the p53 tumor suppressor protein, a sequence-specific DNA-binding protein and stressactivated transcription factor that controls and coordinates the expression of a battery of genes involved in transient growth arrest, DNA and cellular repair, and/or apoptosis (1). The function of the p53 protein is regulated post-translationally by enzymes that catalyze p53 ubiquitination, acetylation, and phosphorylation. In the absence of stress, the specific activity of p53 is suppressed by the action of E3 ubiquitin ligases like MDM2 that promote proteasomal degradation of the protein (2). In response to stress signals like DNA damage, this degradation program is suppressed, and sets of protein kinase pathways, notably ATM, trigger activation of the protein.The mechanisms of p53 activation by phosphorylation at the most evolutionarily conserved phosphoacceptor sites has been assigned both biochemically and genetically. The phosphoacceptor sites in the p53 transactivation domain are the most highly conserved between vertebrates and invertebrates: phosphorylation of p53 at Ser 20 stabilizes the interaction with acetyltransferases like p300 and in turn stimulates DNA-dependent acetylation (3, 4); phosphorylation at Ser 15 can stimulate CBP binding and p53 acetylation (5); and phosphorylation at Thr 18 can both stabilize p300 binding and reduce MDM2 binding (4, 6). The stabilization of p300 relates to the conversion of intrinsically unstructured activation motifs in p53 to a more helical character with a higher affinity for p300 (7). Mice with mutations at the equivalent Ser 20 residue develop spontaneous B-cell lymphomas (8), and Ser 15 mutant transgenes develop spontaneous late onset lymphoma (9). The Ser 392 phosphoacceptor site in the C-terminal domain of p53 is the second most highly conserved class of phosphoacceptor site but only within vertebrates. Increased phosphorylation of p53 at the Ser 392 site occurs in vivo after UV and ionizing radiation (10, 11), and this stimulates the sequence-specific DNA-binding function of p53 (12). Phosphorylation of p53 at Ser 392 enhances the stability of the p53 tetramerization domain (13), and phosphomimetic mutation at codon 392 results in enhanced thermostability of the p53 tetramer (14), providing biophysical evidence for conformational changes of this phosphorylation on p53. Genetic studies in mice have shown that mutation of the CK2 site results in enhanced skin or bladder cancer in response to UV damage or carcinogen exposure (15,16), and mouse embryo fibroblasts from such transgenic mice also have an attenuated p53 transcriptome (17). Further, the enhanced phosphorylation of p53 in the basal/ stem cells of UV-irradiated human skin (11) is attributable to the transcriptional activation of ATM by ⌬Np63 (18). Although these biochemical and genetic studies provide a paradigm for how phosphorylation can regulate p53 protein function at the most highly conserved phosphorylation sites, the effec...

show abstract

Section: In Vitro Kinase Screens Identify a Novel Phosphoacceptor Sitsupporting

confidence: 91%

A Novel p53 Phosphorylation Site within the MDM2 Ubiquitination Signal

Fraser

Vojtěšek

Hupp

2010

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…[3][4][5][6][7] However, MDM2 and MDMX genes have become increasingly prominent as key regulators of p53. 36,37 Consistently, overexpression of MDM2 and MDMX were observed in more than 40% of newly diagnosed myelomas using gene expression profile, suggesting the p53 inactivation in these cases (data not shown). Although we do not refute the previous conclusion established by the preponderance of literature, our results suggest that an extrinsic apoptotic signaling pathway is also a possible route for ATO to induce apoptosis.…”

Section: Discussionsupporting

confidence: 51%

Arsenic trioxide-mediated growth inhibition of myeloma cells is associated with an extrinsic or intrinsic signaling pathway through activation of TRAIL or TRAIL receptor 2

Shi

et al. 2010

Cancer Biology & Therapy

View full text Add to dashboard Cite

“…23,32 Both peptidomimetics 26,[33][34][35][36][37][38][39][40] and small molecules 25,41 have been reported to inhibit the interaction of MDM2-p53 and reactivate the transcriptional pathway; recently the mechanism underpinning the differences in the interactions of peptides and of small molecules has been described. 31,42 Clinical trials with some of these molecules are currently in progress. 32 An advantage that peptide inhibitors have over small molecules in targeting protein interaction surfaces is that they can be fine tuned for greater specificity.…”

Section: Introductionmentioning

confidence: 99%