Restoration of conformation of mutant p53

Green, J.A.; Euler, Mikael von; Abrahmsén, Lars

doi:10.1093/annonc/mdy057

Cited by 9 publications

(6 citation statements)

References 45 publications

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“…It is believed that, like APR-246, the primary mechanism by which COTI-2 acts, is through reactivation of mtp53 protein, thereby restoring its DNA-binding properties and the ability of converted p53 to induce expression of its target genes. 26 , 27 Studies show, however, that COTI-2 may possess anticancer properties that are independent of p53 status, including an ability to inhibit the target of rapamycin (mTOR) pathway and activate AMP-activated protein kinase (AMPK). 26 Another small molecule drug, NSC2287, Reactivation of p53 and Induction of Tumor cell Apoptosis (RITA), also binds to mtp53 protein and restores its proper transcriptional functions.…”

Section: Other Small Molecule Drugs That Act On Mtp53 Proteinmentioning

confidence: 99%

Role of Reactivating Mutant p53 Protein in Suppressing Growth and Metastasis of Triple-Negative Breast Cancer

Berke¹,

Slight²,

Hyder³

2022

OTT

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Tumor suppressor p53 protein (p53) plays a vital role throughout the body to conserve DNA stability and prevent cancer. Normally, wild-type p53 protein (wtp53) is either degraded or bound to a negative regulator and is inactive. When damage to DNA occurs within a cell, p53 protein is induced and causes cell cycle arrest. This gives cells a chance to repair, but if damage is too severe, cells undergo apoptosis and are rejected. Mutations in the p53 gene ( mtp53 ) are associated with a variety of cancers and occur in 70–80% of cases of triple-negative breast cancer (TNBC). Importantly, many mutations occur in the DNA binding domain of p53 gene and the altered mutant p53 protein (mtp53) is subsequently not degraded. High levels of mtp53 protein accumulate within the cell, leading to the development of tumors. Therefore, converting mtp53 protein back into its functional wild-type conformation is a promising means by which to prevent or reverse tumor development. Herein we will briefly examine how tumor suppressor wtp53 exerts its effects, the mechanisms involved in protecting cells that undergo DNA damage and ways in which wtp53 prevents tumorigenesis. Using TNBC as an example, we will describe the use of specific compounds to reactivate mtp53 protein function by reconfiguring its structure and outline the potential benefits of mtp53 protein reactivation. We will also briefly discuss current clinical trials aimed at reactivating mtp53 protein in order to cure certain cancers. Finally, we make the recommendation that greater emphasis should be placed on testing naturally occurring compounds that are generally non-toxic to re-activate mtp53 protein and control progression of TNBC.

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Section: Other Small Molecule Drugs That Act On Mtp53 Proteinmentioning

confidence: 99%

Role of Reactivating Mutant p53 Protein in Suppressing Growth and Metastasis of Triple-Negative Breast Cancer

Berke¹,

Slight²,

Hyder³

2022

OTT

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“…The pathogenic TP53 variants found in our two patients raise the hypothetical possibility of a common mechanism in SDS hematological clonal evolution and tissue malignancies 13,14 . Further molecular and cellular studies are needed to elucidate this complication in the natural history of SDS in order to treat it 15 …”

Section: Discussionmentioning

confidence: 84%

“…13,14 Further molecular and cellular studies are needed to elucidate this complication in the natural history of SDS in order to treat it. 15…”

Section: Ta B L Ementioning

confidence: 99%

Shwachman‐Diamond syndrome and solid tumors: Three new patients from the French Registry for Severe Chronic Neutropenia and literature review

Mitri

Beaupain

Fléjou

et al. 2021

Pediatric Blood & Cancer

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Shwachman-Diamond syndrome with Shwachman-Bodian-Diamond syndrome (SBDS) biallelic variants is a rare disorder that predisposes the carrier to malignant hemopathies but solid-cancer predisposition is poorly known. Among 155 cases entered in the French Registry for Severe Chronic Neutropenia, three were identified with malignant solid tumors (ovary, breast, and esophagus). All cancers occurred during the fifth decade and, despite being localized at diagnosis, were rapidly fatal thereafter.No cancer was observed post transplantation in the 14 HSCT survivors. Based on the literature and our patient data, we can merely advance that this complication is predominantly diagnosed in adults.

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“…12 The pathogenicTP53 variants found in #5254 and #5726 raise the possibility of a hypothetical common mechanism both in SDS hematological clonal evolution as well as in tissue malignancies 13,14 . Further molecular and cellular studies are needed to understand this complication in the natural history of SDS in order to treat it 15 .…”

Section: Discussionmentioning

confidence: 99%

Shwachman–Diamond syndrome and solid tumors: 3 new patients from the French severe chronic neutropenia registry and literature review

Mitri

Beaupain

Fléjou

et al. 2020

Preprint

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Shwachman-Diamond syndrome with Shwachman-Bodian-Diamond syndrome (SBDS) biallelic variants is a rare disorder that predisposes the carrier to malignant hemopathies but solid-cancer predisposition is poorly known. Among 155 cases entered in the French Severe Chronic Neutropenia Registry, three were identified original with malignant solid tumors (ovary, breast and esophagus). All cancers occurred in the fifth decade and, despite being at localized stages at diagnosis, they were rapidly fatal thereafter. No cancer was observed in the 14 HSCT survivors post transplantation. Based on our experience and the literature, age >40 years was the only apparent risk factor.

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Restoration of conformation of mutant p53

Cited by 9 publications

References 45 publications

Role of Reactivating Mutant p53 Protein in Suppressing Growth and Metastasis of Triple-Negative Breast Cancer

Role of Reactivating Mutant p53 Protein in Suppressing Growth and Metastasis of Triple-Negative Breast Cancer

Shwachman‐Diamond syndrome and solid tumors: Three new patients from the French Registry for Severe Chronic Neutropenia and literature review

Shwachman–Diamond syndrome and solid tumors: 3 new patients from the French severe chronic neutropenia registry and literature review

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