Mutant p53: one name, many proteins

doi:10.1101/GAD.190678.112

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Mutant p53: one name, many proteins

Journal Article•DOI•

Mutant p53: one name, many proteins

William A. Freed-Pastor¹, Carol Prives•Institutions (1)

Columbia University¹

15 Jun 2012-Genes & Development (Genes Dev)-Vol. 26, Iss: 12, pp 1268-1286

TL;DR: Mechanisms by which Mutant p53 exerts its cellular effects are reviewed, with a particular focus on the burgeoning mutant p53 transcriptome, and the biological and clinical consequences of mutant p 53 gain of function are discussed.

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Abstract: There is now strong evidence that mutation not only abrogates p53 tumor-suppressive functions, but in some instances can also endow mutant proteins with novel activities. Such neomorphic p53 proteins are capable of dramatically altering tumor cell behavior, primarily through their interactions with other cellular proteins and regulation of cancer cell transcriptional programs. Different missense mutations in p53 may confer unique activities and thereby offer insight into the mutagenic events that drive tumor progression. Here we review mechanisms by which mutant p53 exerts its cellular effects, with a particular focus on the burgeoning mutant p53 transcriptome, and discuss the biological and clinical consequences of mutant p53 gain of function.

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Journal Article•DOI•

Mutant p53 in Cancer: New Functions and Therapeutic Opportunities

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Patricia A.J. Muller¹, Karen H. Vousden•Institutions (1)

University of Leicester¹

17 Mar 2014-Cancer Cell

TL;DR: There is growing evidence that these mutant p53s have both lost wild-type p53 tumor suppressor activity and gained functions that help to contribute to malignant progression.

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1,235 citations

Journal Article•DOI•

Putting p53 in Context

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Edward R. Kastenhuber¹, Scott W. Lowe¹, Scott W. Lowe²•Institutions (2)

Memorial Sloan Kettering Cancer Center¹, Howard Hughes Medical Institute²

07 Sep 2017-Cell

TL;DR: TP53 is the most frequently mutated gene in human cancer and must be interpreted to understand how cell type, mutation profile, and epigenetic cell state dictate outcomes, and how might it restore its tumor-suppressive activities in cancer.

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1,215 citations

Cites background from "Mutant p53: one name, many proteins..."

...Loss of function is a common characteristic across all cancer-associated p53 mutants, given the failure of most mutants to induce apoptosis (Freed-Pastor and Prives, 2012)....
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...It remains difficult to reconcile how so many distinct yet selective protein-protein interactions can occur for disparate mutant proteins (reviewed in Freed-Pastor and Prives, 2012)....
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Journal Article•DOI•

How does p53 induce apoptosis and how does this relate to p53-mediated tumour suppression?

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Brandon J. Aubrey¹, Gemma L. Kelly², Gemma L. Kelly¹, Ana Janic², Ana Janic¹, Marco J Herold², Marco J Herold¹, Andreas Strasser¹, Andreas Strasser² - Show less +5 more•Institutions (2)

Walter and Eliza Hall Institute of Medical Research¹, University of Melbourne²

01 Jan 2018-Cell Death & Differentiation

TL;DR: Current understanding of the mechanisms by which p53 induces cell death is discussed and how this affects p53-mediated tumour suppression and the response of malignant cells to anticancer therapy is discussed.

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Abstract: The tumour suppressor gene TP53 is mutated in ~50% of human cancers. In addition to its function in tumour suppression, p53 also plays a major role in the response of malignant as well as nontransformed cells to many anticancer therapeutics, particularly those that cause DNA damage. P53 forms a homotetrameric transcription factor that is reported to directly regulate ~500 target genes, thereby controlling a broad range of cellular processes, including cell cycle arrest, cell senescence, DNA repair, metabolic adaptation and cell death. For a long time, induction of apoptotic death in nascent neoplastic cells was regarded as the principal mechanism by which p53 prevents tumour development. This concept has, however, recently been challenged by the findings that in striking contrast to Trp53-deficient mice, gene-targeted mice that lack the critical effectors of p53-induced apoptosis do not develop tumours spontaneously. Remarkably, even mice lacking all mediators critical for p53-induced apoptosis, G1/S boundary cell cycle arrest and cell senescence do not develop any tumours spontaneously. In this review we discuss current understanding of the mechanisms by which p53 induces cell death and how this affects p53-mediated tumour suppression and the response of malignant cells to anticancer therapy.

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699 citations

Федеральное государственное бюджетное учреждение «Научно-исследовательский институт комплексных проблем сердечно-сосудистых заболеваний» Сибирского отделения Российской академии медицинских наук, Кемерово, Россия

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S. V. Ivanov, A. N. Sumin, Y. V. Kazachek, D. E. Philipiev, S. M. Gusev, E. S. Malyshenko, L. S. Barbarash - Show less +3 more

01 Jan 2013

TL;DR: The outcomes of CAD surgical treatment were improved in this group of patients due to the implementation of a mul-assisted revascularization of coronary and non-coronary arteries.

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Abstract: Results. The incidence rate of significant non-cardiac occlusive stenotic lesions in patients with coronary artery disease (CAD), who had to undergo CABG, was 15,84 %. Simultaneous revascularization of coronary and non-coronary arteries was performed in 2,46 % of patients with CAD and PolyVD and multi-stage surgical proced ures were chosen in other cases. Conclusions. The outcomes of CAD surgical treatment were improved in this group of patients due to the implementation of a mul-

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506 citations

Additional excerpts

...D17S796 5 / -CAATGGAACCAAATGTGGTC-3′ 5 / -AGTCCGATAATGCCAGGATG-3′ 63 144–174 — [212]...
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...Известно, например, что избыточная экспрессия р53 в опухолевой ткани не предсказывает ухудшения выживаемости пациентов с ДВККЛ в условиях современной терапии заболевания с применением моноклональных антител [52; 212; 332]....
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Journal Article•DOI•

Current Challenges and Opportunities in Treating Glioblastoma

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Andrea Shergalis¹, Armand Bankhead¹, Urarika Luesakul¹, Nongnuj Muangsin¹, Nouri Neamati¹ - Show less +1 more•Institutions (1)

University of Michigan¹

01 Jul 2018-Pharmacological Reviews

TL;DR: Novel drug delivery methods, including nanoparticles and prodrugs and computational multi-parameter optimization to assess the blood-brain barrier (BBB) permeability of small molecules in clinical trials for GBM treatment are discussed.

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Abstract: Glioblastoma multiforme (GBM), the most common and aggressive primary brain tumor, has a high mortality rate despite extensive efforts to develop new treatments. GBM exhibits both intra- and intertumor heterogeneity, lending to resistance and eventual tumor recurrence. Large-scale genomic and proteomic analysis of GBM tumors has uncovered potential drug targets. Effective and "druggable" targets must be validated to embark on a robust medicinal chemistry campaign culminating in the discovery of clinical candidates. Here, we review recent developments in GBM drug discovery and delivery. To identify GBM drug targets, we performed extensive bioinformatics analysis using data from The Cancer Genome Atlas project. We discovered 20 genes, BOC, CLEC4GP1, ELOVL6, EREG, ESR2, FDCSP, FURIN, FUT8-AS1, GZMB, IRX3, LITAF, NDEL1, NKX3-1, PODNL1, PTPRN, QSOX1, SEMA4F, TH, VEGFC, and C20orf166AS1 that are overexpressed in a subpopulation of GBM patients and correlate with poor survival outcomes. Importantly, nine of these genes exhibit higher expression in GBM versus low-grade glioma and may be involved in disease progression. In this review, we discuss these proteins in the context of GBM disease progression. We also conducted computational multi-parameter optimization to assess the blood-brain barrier (BBB) permeability of small molecules in clinical trials for GBM treatment. Drug delivery in the context of GBM is particularly challenging because the BBB hinders small molecule transport. Therefore, we discuss novel drug delivery methods, including nanoparticles and prodrugs. Given the aggressive nature of GBM and the complexity of targeting the central nervous system, effective treatment options are a major unmet medical need. Identification and validation of biomarkers and drug targets associated with GBM disease progression present an exciting opportunity to improve treatment of this devastating disease.

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470 citations

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References

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Journal Article•DOI•

Hallmarks of cancer: the next generation.

[...]

Douglas Hanahan¹, Robert A. Weinberg²•Institutions (2)

ISREC¹, Massachusetts Institute of Technology²

04 Mar 2011-Cell

TL;DR: Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer.

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51,099 citations

Journal Article•DOI•

Surfing the p53 network

[...]

Bert Vogelstein¹, David P. Lane², Arnold J. Levine³•Institutions (3)

Howard Hughes Medical Institute¹, University of Dundee², Rockefeller University³

16 Nov 2000-Nature

TL;DR: The p53 tumour-suppressor gene integrates numerous signals that control cell life and death, and the disruption of p53 has severe consequences when a highly connected node in the Internet breaks down.

...read moreread less

Abstract: The p53 tumour-suppressor gene integrates numerous signals that control cell life and death. As when a highly connected node in the Internet breaks down, the disruption of p53 has severe consequences.

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6,605 citations

"Mutant p53: one name, many proteins..." refers background in this paper

...In addition to the early findings by the Vogelstein group (Vogelstein et al. 2000; Petitjean et al. 2007b), literally thousands of studies have now confirmed that TP53 mutations are not restricted to colorectal cancer, but are present in >50% of all human tumors, although the extent of p53 mutation…...
[...]
...In addition to the early findings by the Vogelstein group (Vogelstein et al. 2000; Petitjean et al. 2007b), literally thousands of studies have now confirmed that TP53 mutations are not restricted to colorectal cancer, but are present in >50% of all human tumors, although the extent of p53 mutation varies with the tumor type....
[...]
...1 and encodes the p53 protein, is the most frequent target for mutation in human cancer, with greater than half of all tumors exhibiting mutation at this locus (Vogelstein et al. 2000; Petitjean et al. 2007b)....
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Journal Article•DOI•

Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours

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Lawrence A. Donehower¹, Michele Harvey¹, Betty L. Slagle¹, Mark J. McArthur, Charles A. Montgomery¹, Janet S. Butel¹, Allan Bradley¹ - Show less +3 more•Institutions (1)

Baylor College of Medicine¹

19 Mar 1992-Nature

TL;DR: Observations indicate that a normal p53 gene is dispensable for embryonic development, that its absence predisposes the animal to neoplastic disease, and that an oncogenic mutant form of p53 is not obligatory for the genesis of many types of tumours.

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Abstract: Mutations in the p53 tumour-suppressor gene are the most frequently observed genetic lesions in human cancers. To investigate the role of the p53 gene in mammalian development and tumorigenesis, a null mutation was introduced into the gene by homologous recombination in murine embryonic stem cells. Mice homozygous for the null allele appear normal but are prone to the spontaneous development of a variety of neoplasms by 6 months of age. These observations indicate that a normal p53 gene is dispensable for embryonic development, that its absence predisposes the animal to neoplastic disease, and that an oncogenic mutant form of p53 is not obligatory for the genesis of many types of tumours.

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4,710 citations

"Mutant p53: one name, many proteins..." refers background in this paper

...A mouse model in which p53 was disrupted by homologous recombination revealed that although p53 / mice were developmentally normal (for the most part), they were extremely cancer-prone (Donehower et al. 1992; Attardi and Jacks 1999)....
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Journal Article•DOI•

Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms

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David Malkin¹, Frederick P. Li¹, Frederick P. Li², Louise C. Strong, Joseph F. Fraumeni², Camille E. Nelson¹, Camille E. Nelson², David H. Kim¹, Jayne Kassel¹, Magdalena A. Gryka¹, Farideh Z. Bischoff³, Michael A. Tainsky³, Stephen H. Friend¹ - Show less +9 more•Institutions (3)

Harvard University¹, National Institutes of Health², University of Texas MD Anderson Cancer Center³

30 Nov 1990-Science

TL;DR: Germ line p53 mutations have been detected in all five LFS families analyzed and can now be examined in additional families with LFS, and in other cancer patients and families with clinical features that might be attributed to the mutation.

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Abstract: Familial cancer syndromes have helped to define the role of tumor suppressor genes in the development of cancer. The dominantly inherited Li-Fraumeni syndrome (LFS) is of particular interest because of the diversity of childhood and adult tumors that occur in affected individuals. The rarity and high mortality of LFS precluded formal linkage analysis. The alternative approach was to select the most plausible candidate gene. The tumor suppressor gene, p53, was studied because of previous indications that this gene is inactivated in the sporadic (nonfamilial) forms of most cancers that are associated with LFS. Germ line p53 mutations have been detected in all five LFS families analyzed. These mutations do not produce amounts of mutant p53 protein expected to exert a trans-dominant loss of function effect on wild-type p53 protein. The frequency of germ line p53 mutations can now be examined in additional families with LFS, and in other cancer patients and families with clinical features that might be attributed to the mutation.

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3,662 citations

"Mutant p53: one name, many proteins..." refers background in this paper

...Mdm2, an E3 ubiquitin ligase, is the major negative regulator of p53 and serves to keep p53 levels in check under unstressed conditions (Poyurovsky and Prives 2006; Manfredi 2010; Marine and Lozano 2010)....
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Journal Article•DOI•

Live or let die: the cell's response to p53

[...]

Karen H. Vousden¹, Xin Lu²•Institutions (2)

National Institutes of Health¹, Ludwig Institute for Cancer Research²

01 Aug 2002-Nature Reviews Cancer

TL;DR: Understanding the complex mechanisms that regulate whether or not a cell dies in response to p53 will ultimately contribute to the development of therapeutic strategies to repair the apoptotic p53 response in cancers.

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Abstract: Compared with many normal tissues, cancer cells are highly sensitized to apoptotic signals, and survive only because they have acquired lesions — such as loss of p53 — that prevent or impede cell death. We are now beginning to understand the complex mechanisms that regulate whether or not a cell dies in response to p53 — insights that will ultimately contribute to the development of therapeutic strategies to repair the apoptotic p53 response in cancers.

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3,242 citations

"Mutant p53: one name, many proteins..." refers background in this paper

...Following activation, wild-type p53 normally functions as a sequence-specific transcription factor to inhibit cell cycle progression, promote senescence, or induce apoptotic cell death (Prives and Hall 1999; Vousden and Lu 2002; Vousden and Prives 2009)....
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...Wild-type p53 can be activated by a number of cellular stressors, including DNA damage, hypoxia, and oncogene activation (Vousden and Lu 2002)....
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...Wild-type p53 can be activated by a number of cellular stressors, including DNA damage, hypoxia, and oncogene activation (Vousden and Lu 2002)....
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...…of p53 activation such as cell cycle arrest (CDKN1A, MIR34A, etc.), senescence (CDKN1A, PAI1, etc.), apoptosis (PUMA, BAX, etc.), and metabolic processes (TIGAR, SCO2, GLS2, etc.) (Prives and Hall 1999; Vousden and Lu 2002; Riley et al. 2008; Vousden and Prives 2009; Vousden and Ryan 2009)....
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