A Designed Inhibitor of p53 Aggregation Rescues p53 Tumor Suppression in Ovarian Carcinomas

Soragni, Alice; Janzen, Deanna M.; Johnson, Lisa M.; Lindgren, Anne; NguyenThai, Quynh-Anh; Tiourin, E.; Soriaga, A.B.; Lü, Jing; Jiang, Lin; Faull, Kym F.; Pellegrini, Matteo; Memarzadeh, Sanaz; Eisenberg, David

doi:10.1016/j.ccell.2015.12.002

Cited by 297 publications

(390 citation statements)

References 59 publications

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“…For NM, as with many other amyloid-forming proteins such as TTR (48), Tau (49), and p53 (50), much of the detailed structural work has been focused on small peptides derived from aggregation-prone regions of a fulllength protein. The peptide GNNQQNY corresponds to residues 7 to 13 of the 253-residue-long NM.…”

Section: Discussionmentioning

confidence: 99%

Combining DNP NMR with segmental and specific labeling to study a yeast prion protein strain that is not parallel in-register

Frederick

Michaelis

Caporini

et al. 2017

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

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The yeast prion protein Sup35NM is a self-propagating amyloid. Despite intense study, there is no consensus on the organization of monomers within Sup35NM fibrils. Some studies point to a β-helical arrangement, whereas others suggest a parallel inregister organization. Intermolecular contacts are often determined by experiments that probe long-range heteronuclear contacts for fibrils templated from a 1:1 mixture of 13 C-and 15 N-labeled monomers. However, for Sup35NM, like many large proteins, chemical shift degeneracy limits the usefulness of this approach. Segmental and specific isotopic labeling reduce degeneracy, but experiments to measure long-range interactions are often too insensitive. To limit degeneracy and increase experimental sensitivity, we combined specific and segmental isotopic labeling schemes with dynamic nuclear polarization (DNP) NMR. Using this combination, we examined an amyloid form of Sup35NM that does not have a parallel in-register structure. The combination of a small number of specific labels with DNP NMR enables determination of architectural information about polymeric protein systems. (2), is an amyloid form of the translation termination factor Sup35 (3). The amyloid fold is polymeric fiber of protein monomers that is rich in β-sheets that run perpendicular to the fiber axis. Amyloid formation sequesters Sup35 from the ribosome, changing the rate of stop-codon read-through and creating a variety of new yeast phenotypes (4,5). Different regions of the Sup35 protein are responsible for prion templating, prion inheritance, and translation termination. The N-terminal domain "N" is Q/N-rich and required for the formation and templating of amyloid. The highly charged K/E-rich middle domain "M" promotes solubility in the nonprion form and is required for chaperone-mediated prion inheritance (6, 7). The C-terminal domain is necessary and sufficient for translation termination. The N and M domains together, NM, contain all of the necessary features to act as an amyloid-based prion.A wide variety of approaches have been used to investigate Sup35 prion structures, but a consensus structural picture has yet to emerge. Amyloids are notoriously difficult to study, mainly because they are insoluble yet noncrystalline and are therefore not easily amenable to traditional structural biology methods. In all models, at least some part of the N domain is involved in the amyloid fold (8-11), and most of the M domain is thought to be solvent-accessible and intrinsically disordered (11-13). However, there are two conflicting models of how monomers of NM are arranged in amyloid fibers. In one model, called the β-helical model, monomers make intermolecular contacts in discrete regions, with the region in-between making intramolecular contacts. This model is supported by the patterns of interaction and cross-linking determined from a series of site-directed mutants (8). The work has the caveat that mutations may perturb the fibril structure. However, fibers made from the mutated versions of the protein ca...

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Section: Discussionmentioning

confidence: 99%

Combining DNP NMR with segmental and specific labeling to study a yeast prion protein strain that is not parallel in-register

Frederick

Michaelis

Caporini

et al. 2017

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

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“…Bioinformatic scanning of the p53 sequence suggested that a conserved aggregation-prone peptide (residues 251-258) within the DNA-binding domain of WT p53 might represent the nucleation site for aggregate formation (Fig. 3) (Xu et al 2011;Ghosh et al 2014;Rangel et al 2014;Soragni et al 2016). Further studies of this short segment using synthetic peptides revealed that it formed amyloid-like aggregates with WT p53 and coaggregated with p63/p73, leading to the inhibition of their functions (Xu et al 2011;Ghosh et al 2014).…”

Section: Mechanisms Underlying the Prion-like Aggregation Of Tumor Sumentioning

confidence: 99%

“…R248Q mutant p53 has been previously shown to aggregate in breast cancer biopsies and cell lines (Levy et al 2011;Ano Bom et al 2012). RecACp53 was also able to reduce in vivo xenograft growth and metastasis (Soragni et al 2016). RecACp53 had no effects when the cells had WT p53.…”

Section: New Approaches For Cancer Therapy Involving P53 Aggregationmentioning

confidence: 99%

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Aggregation and Prion-Like Properties of Misfolded Tumor Suppressors: Is Cancer a Prion Disease?

Costa

Oliveira

Cino

et al. 2016

Cold Spring Harb Perspect Biol

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Prion diseases are disorders that share several characteristics that are typical of many neurodegenerative diseases. Recently, several studies have extended the prion concept to pathological aggregation in malignant tumors involving misfolded p53, a tumor-suppressor protein. The aggregation of p53 and its coaggregation with p53 family members, p63 and p73, have been shown. Certain p53 mutants exert a dominant-negative regulatory effect on wild-type (WT) p53. The basis for this dominant-negative effect is that amyloid-like mutant p53 converts WT p53 into an aggregated species, leading to a gain-of-function (GoF) phenotype and the loss of its tumor-suppressor function. Recently, it was shown that p53 aggregates can be internalized by cells and can coaggregate with endogenous p53, corroborating the prion-like properties of p53 aggregates. The prion-like behavior of oncogenic p53 mutants provides an explanation for its dominant-negative and GoF properties, including the high metastatic potential of cancer cells carrying p53 mutations. The inhibition of p53 aggregation appears to represent a promising target for therapeutic intervention in patients with malignant tumors.

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“…Advancement in technology, structural proteomics and information from sequencing data have enabled more efficient screening and validation of tumor-associated antigens (TAAs) that may be targeted by T cells (Battaglia and Muhitch, 2016). For instance, the understanding of the structure of tumor antigen p53, in ovarian cancer, led to the design of an effective p53 peptide inhibitor (Soragni et al, 2016). Structural understanding of TAAs recognized by effector T cells and design of therapies based on the TCR-pMHC interaction could be useful in combination with ACT.…”

Section: T Cell Receptorsmentioning

confidence: 99%

Adoptive immunotherapy via CD4+ versus CD8+ T cells

Phan-Lai

2016

Biomed Res Ther

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Abstract-The goal of cancer immunotherapy is to induce specific and durable antitumor immunity. Adoptive T cell therapy (ACT) has garnered wide interest, particularly in regard to strategies to improve T cell efficacy in trials. There are many types of T cells (and subsets) which can be selected for use in ACT. CD4+ T cells are critical for the regulation, activation and aid of host defense mechanisms and, importantly, for enhancing the function of tumor-specific CD8+ T cells. To date, much research in cancer immunotherapy has focused on CD8+ T cells, in melanoma and other cancers. Both CD4+ T cells and CD8+ T cells have been evaluated as ACT in mice and humans, and both are effective at eliciting antitumor responses. IL-17 producing CD4+ T cells are a new subset of CD4+ T cells to be evaluated in ACT models. This review discusses the benefits of adoptive immunotherapy mediated by CD8+ and CD4+ cells. It also discusses the various type of T cells, source of T cells, and ex vivo cytokine growth factors for augmenting clinical efficacy of ACT.

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A Designed Inhibitor of p53 Aggregation Rescues p53 Tumor Suppression in Ovarian Carcinomas

Cited by 297 publications

References 59 publications

Combining DNP NMR with segmental and specific labeling to study a yeast prion protein strain that is not parallel in-register

Combining DNP NMR with segmental and specific labeling to study a yeast prion protein strain that is not parallel in-register

Aggregation and Prion-Like Properties of Misfolded Tumor Suppressors: Is Cancer a Prion Disease?

Adoptive immunotherapy via CD4+ versus CD8+ T cells

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