The Tumor Suppressor p53: From Structures to Drug Discovery

Joerger, A.C.; Fersht, Alan R.

doi:10.1101/cshperspect.a000919

Cited by 289 publications

(286 citation statements)

References 157 publications

(174 reference statements)

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“…The intrinsic disorder of the TAD and NRD enable binding of multiple partners with varied strengths. Moreover, the flexible nature of the entire p53 molecule and the intrinsic disorder of TAD and NRD domains assist p53's binding partners in forming multi-point interactions with p53 in both the TAD and the NRD [25]. However, the disorder of these domains also limits the ability of traditional experimental methods to investigate the structure of p53 or its disordered domains, particularly when not bound to partners.…”

Section: P53mentioning

confidence: 99%

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Intrinsically Disordered Proteins: Where Computation Meets Experiment

2014

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Proteins are heteropolymers that play important roles in virtually every biological reaction. While many proteins have well-defined three-dimensional structures that are inextricably coupled to their function, intrinsically disordered proteins (IDPs) do not have a well-defined structure, and it is this lack of structure that facilitates their function. As many IDPs are involved in essential cellular processes, various diseases have been linked to their malfunction, thereby making them important drug targets. In this review we discuss methods for studying IDPs and provide examples of how computational methods can improve our understanding of IDPs. We focus on two intensely studied IDPs that have been implicated in very different pathologic pathways. The first, p53, has been linked to over 50% of human cancers, and the second, Amyloid-β (Aβ), forms neurotoxic aggregates in the brains of patients with Alzheimer's disease. We use these representative proteins to illustrate some of the challenges associated with studying IDPs and demonstrate how computational tools can be fruitfully applied to arrive at a more comprehensive understanding of these fascinating heteropolymers. OPEN ACCESSPolymers 2014, 6 2685

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Section: P53mentioning

confidence: 99%

“…Its involvement in so many cellular processes ensures that mutations in p53 have widespread effects. In fact, 50% of cancers involve an inactivating mutation of p53 [108], and the apoptotic pathways controlled by p53 are impaired in the remaining cancers [25,108].…”

Section: P53mentioning

confidence: 99%

Intrinsically Disordered Proteins: Where Computation Meets Experiment

2014

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“…The N-terminus trans-activation domain (TA) is involved in selecting its interaction with either ubiquitin ligases or with transcriptional cofactors, and its specifity is determined by the phosphorylation pattern. The DNA binding domain (DBD) is the p53 central region, and the C-terminus has and oligomerization (OD) and a regulatory subregions [51]. Next, we asked which of these p53 regions was implicated in its binding to VRK1.…”

Section: The P53 Dna Binding Domain (Dbd) Interacts With Vrk1mentioning

confidence: 99%

VRK1 interacts with p53 forming a basal complex that is activated by UV‐induced DNA damage

et al. 2014

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a b s t r a c t DNA damage immediate cellular response requires the activation of p53 by kinases. We found that p53 forms a basal stable complex with VRK1, a Ser-Thr kinase that responds to UV-induced DNA damage by specifically phosphorylating p53. This interaction takes place through the p53 DNA binding domain, and frequent DNA-contact mutants of p53, such as R273H, R248H or R280K, do not disrupt the complex. UV-induced DNA damage activates VRK1, and is accompanied by phosphorylation of p53 at Thr-18 before it accumulates. We propose that the VRK1-p53 basal complex is an early-warning system for immediate cellular responses to DNA damage. Structured summary of protein interactions:VRK1 physically interacts with p53 by anti bait coimmunoprecipitation (1, 2, 3, 4) VRK1 physically interacts with p53 by pull down (1,2,3)

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“…TP53 mutation studies have applied a variety of analyses, including molecular epidemiology, clinical surveys, and structural analyses (7,8). Such studies require highly curated TP53 mutation data from the Locus Specific Database (LSDB) established and maintained since 1989 (9, 10).…”

mentioning

confidence: 99%

Data-driven unbiased curation of the TP53 tumor suppressor gene mutation database and validation by ultradeep sequencing of human tumors

Edlund

Larsson

Ameur

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Cancer mutation databases are expected to play central roles in personalized medicine by providing targets for drug development and biomarkers to tailor treatments to each patient. The accuracy of reported mutations is a critical issue that is commonly overlooked, which leads to mutation databases that include a sizable number of spurious mutations, either sequencing errors or passenger mutations. Here we report an analysis of the latest version of the TP53 mutation database, including 34,453 mutations. By using several data-driven methods on multiple independent quality criteria, we obtained a quality score for each report contributing to the database. This score can now be used to filter for high-confidence mutations and reports within the database. Sequencing the entire TP53 gene from various types of cancer using next-generation sequencing with ultradeep coverage validated our approach for curation. In summary, 9.7% of all collected studies, mostly comprising numerous tumors with multiple infrequent TP53 mutations, should be excluded when analyzing TP53 mutations. Thus, by combining statistical and experimental analyses, we provide a curated mutation database for TP53 mutations and a framework for mutation database analysis.cancer genetics | genomic | locus-specific database C onventional sequencing using Sanger's methodology has allowed for the discovery of genetic alterations in cancer genes (1). Next-generation sequencing (NGS) techniques have expanded this knowledge by providing a more complete description of each type of alteration, including copy-number variations, translocations, and missense mutations (2, 3). The majority of these mutations are passenger mutations (or hitchhiking mutations) that have no active role in cancer progression and are only coselected with the driver mutations (4).Since the first publication on TP53 mutations in 1989, more than 2,700 articles have been published describing more than 35,000 TP53 mutations in various tumor types and cell lines (5, 6). TP53 mutation studies have applied a variety of analyses, including molecular epidemiology, clinical surveys, and structural analyses (7,8). Such studies require highly curated TP53 mutation data from the Locus Specific Database (LSDB) established and maintained since 1989 (9, 10).The unique feature of TP53 compared with other tumor-suppressor genes is its mode of inactivation. Although most tumorsuppressor genes are inactivated by mutations, leading to absence of the protein (or synthesis of a truncated product), more than 80% of TP53 alterations are missense mutations encoding a stable full-length protein (11). Moreover, each tumor generally harbors a single mutation in the TP53 gene that reduces the transactivation activity of the TP53 protein, leading to loss of its antiproliferative and proapoptotic properties.Previous studies have raised concerns about the accuracy of the various TP53 databases, because they include all mutations published in peer-reviewed journals (12)(13)(14). Statistical analysis showed that the use of n...

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The Tumor Suppressor p53: From Structures to Drug Discovery

Cited by 289 publications

References 157 publications

Intrinsically Disordered Proteins: Where Computation Meets Experiment

Intrinsically Disordered Proteins: Where Computation Meets Experiment

VRK1 interacts with p53 forming a basal complex that is activated by UV‐induced DNA damage

Data-driven unbiased curation of the TP53 tumor suppressor gene mutation database and validation by ultradeep sequencing of human tumors

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