Switching on p53: an essential role for protein phosphorylation?

Loughery, Jayne; Meek, David W.

doi:10.7750/biodiscovery.2013.8.1

Cited by 30 publications

(39 citation statements)

References 205 publications

(298 reference statements)

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“…In order to understand the physical reasons underpinning the disruption of p53-MDM2 interactions upon p53 phosphorylation, 10 we carried out Brownian dynamics simulations of the interaction of the N-terminal domain of MDM2 protein (residues 25-109) with wild-type p53 peptide and its Thr18 and Ser20 phosphorylated counterparts. We partitioned the resulting interaction landscapes into basins of attraction, wherein the peptide interaction is largely associative, and determined the molecular configurations corresponding to the peptide MDM2 encounter complex in these basins, with no prior knowledge of the peptide-bound complex.…”

Section: Discussionmentioning

confidence: 99%

“…9 p53 phosphorylation, in particular at its N-terminal trans-activation domain (TAD), underpins its uncoupling from the MDM2 protein and is likely to play a significant role in modulating interactions with other transcriptional components. 10 Over 18 phosphoacceptor sites were reported for p53 structural domains, 11 most of them are modified in response to cellular stress. 12 Phosphorylation of the Ser15, Thr18 and Ser20 residues in the TAD region is believed to be key to the rapid uncoupling of p53 and MDM2 10,[13][14][15] while phosphorylation of the Ser6 and Ser9 residues is likely to mediate interaction of p53 with Smad proteins which is important for the contribution of p53 to transforming growth factor b signaling (TGF-b).…”

Section: Introductionmentioning

confidence: 99%

“…10 Over 18 phosphoacceptor sites were reported for p53 structural domains, 11 most of them are modified in response to cellular stress. 12 Phosphorylation of the Ser15, Thr18 and Ser20 residues in the TAD region is believed to be key to the rapid uncoupling of p53 and MDM2 10,[13][14][15] while phosphorylation of the Ser6 and Ser9 residues is likely to mediate interaction of p53 with Smad proteins which is important for the contribution of p53 to transforming growth factor b signaling (TGF-b). 16 Interestingly, Ser15, Thr18 and Ser20 residues were found to be highly conserved in humans and urochordates 17 and therefore their role in modulating p53-MDM2 interactions has received much attention.…”

Section: Introductionmentioning

confidence: 99%

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A spatiotemporal characterization of the effect of p53 phosphorylation on its interaction with MDM2

et al. 2015

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T he interaction of p53 and MDM2 is modulated by the phosphorylation of p53. This mechanism is key to activating p53, yet its molecular determinants are not fully understood. To study the spatiotemporal characteristics of this molecular process we carried out Brownian dynamics simulations of the interactions of the MDM2 protein with a p53 peptide in its wild type state and when phosphorylated at Thr18 (pThr18) and Ser20 (pSer20). We found that p53 phosphorylation results in concerted changes in the topology of the interaction landscape in the diffusively bound encounter complex domain. These changes hinder phosphorylated p53 peptides from binding to MDM2 well before reaching the binding site. The underlying mechanism appears to involve shift of the peptide away from the vicinity of the MDM2 protein, peptide reorientation, and reduction in peptide residence time relative to wild-type p53 peptide. pThr18 and pSr20 p53 peptides experience reduction in residence times by factors of 13.6 and 37.5 respectively relative to the wild-type p53 peptide, indicating a greater role for Ser20 phosphorylation in abrogating p53 MDM2 interactions. These detailed insights into the effect of phosphorylation on molecular interactions are not available from conventional experimental and theoretical approaches and open up new avenues that incorporate molecular interaction dynamics, for stabilizing p53 against MDM2, which is a major focus of anticancer drug lead development.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A spatiotemporal characterization of the effect of p53 phosphorylation on its interaction with MDM2

et al. 2015

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“…In addition to the vast number of protein-protein interactions, p53 is also subjected to covalent modifications such as phosphorylation that can regulate its specific activity [37]. Post-translational modifications (PTMs) are essential for signalling as they affect protein turnover, stability, localisation but also interaction properties and thereby affect deeply the protein function.…”

Section: Post-translational Modificationsmentioning

confidence: 99%

Evolution of Conformational Disorder & Diversity of the P53 Interactome

Huart¹,

Hupp²

2013

Biodiscovery

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The tumour suppressor p53 is now known to be an ancient transcription factor that had already evolved interaction sites with its partner protein MDM2 at the dawn of multi-cellular eukaryotic animal life. The billionyear life history of the p53-MDM2 axis has permitted significant time for the proteins to integrate into a distinct range of cellular pathways including binding to hundreds of genomic promoters and regulatory protein-protein interactions with hundreds of distinct functions. This long age of p53 allows us to understand how the protein can regulate a range of functions such as energy generation of the cell, cell motility, genome integrity, virus infection, immune cell response, ageing, and oxidative stress. Due to this deep integration of p53 into the core of eukaryotic life, it is not surprising that the p53 pathway requires inactivation in order for human cancer cells to evade the normal growth controlling processes that have been shaped through evolution by natural selection. This review will focus on the emerging concepts in the protein science field that shed light on p53 protein evolution and function including the nature of thermodynamically unstable regulatory proteins and the growing realisation that the majority of protein-protein interactions in complex eukaryotic cells are driven by intrinsically unstructured and weakly interacting peptide motifs. These concepts help to explain how the vast number of dynamic and specific protein-protein interactions in the p53 pathway evolved, suggest how amino acid modifications like phosphorylation or acetylation in turn evolved to regulate dynamically the p53 interactome, and finally reveal therapeutic strategies for targeting the p53 interactome in human cancers. Intrinsic disorder: the rise of a new dogma in protein science that impacts upon our understanding of p53As biologists or biochemists, we have all learned the structure-function paradigm that proteins display different levels of organisation: a "primary" linear sequence on which depends local spatial "secondary" arrangements stabilised by a three dimensional compact structure, usually referred as globular protein or called native fold, i.e. the biologically active form of the protein. Upon this structure-function concept several protein-protein interaction (PPI) models have been developed such as the recent Nobel Prize awarded on solving the structure of a ribosome. It is perhaps not a co-incidence that a major advance on the road to acquire the structure of this prokaryotic multi-protein complex was the decision to switch to purifying ribosomal proteins from thermophilic bacteria which are more suitable to form stable structures using current experimental methodologies. More "unstable" ribosomal complexes from, for example, higher eukaryotes are not suitable for such crystallographic

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“…While we will briefly discuss how this occurs in response to DNA damage, the post-translational modifications that stabilise and activate p53 have been discussed in greater detail by David Meek and colleagues in the last issue of BioDiscovery [9].…”

mentioning

confidence: 99%

Distinct target genes and effector processes appear to be critical for p53-activated responses to acute DNA damage versus p53-mediated tumour suppression

Valente¹,

Strasser²

2013

Biodiscovery

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The p53 tumour suppressor is the most frequently mutated gene in human cancer. This transcription factor can be activated by diverse cellular stresses, including DNA damage and oncogene activation. Through transcriptional induction of appropriate target genes, p53 can stimulate activity in a broad range of effector pathways, most notably cell cycle arrest, cellular senescence and apoptotic cell death. Insensitivity to cell death-inducing signals and deregulated proliferation are two key hallmarks of cancer cells. Given that p53 inhibits proliferation and induces apoptosis, it was widely believed that these processes are the most critical ones for p53-mediated tumour suppression. However, this dogma has been challenged. In striking contrast to p53-deficient mice, which all develop tumours before 250 days of age, mutant mice in which expression of the p53 target genes that are critical for induction of cell cycle arrest and apoptosis is impaired or abrogated are not cancer-prone. This demonstrates that distinct effector processes are critical for the p53-mediated acute response to DNA damage versus p53-mediated tumour suppression. The discovery that cell cycle arrest, senescence and apoptosis are not essential for p53-mediated tumour suppression re-launches the search for the p53 target genes and effector processes that are critical to prevent tumour development, with coordination of DNA repair being a leading contender.

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Switching on p53: an essential role for protein phosphorylation?

Cited by 30 publications

References 205 publications

A spatiotemporal characterization of the effect of p53 phosphorylation on its interaction with MDM2

A spatiotemporal characterization of the effect of p53 phosphorylation on its interaction with MDM2

Evolution of Conformational Disorder & Diversity of the P53 Interactome

Distinct target genes and effector processes appear to be critical for p53-activated responses to acute DNA damage versus p53-mediated tumour suppression

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