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The Function of the Mutant p53-R175H in Cancer.

ABSTRACT: Wild-type p53 is known as "the guardian of the genome" because of its function of inducing DNA repair, cell-cycle arrest, and apoptosis, preventing the accumulation of gene mutations. TP53 is highly mutated in cancer cells and most TP53 hotspot mutations are missense mutations. Mutant p53 proteins, encoded by these hotspot mutations, lose canonical wild-type p53 functions and gain functions that promote cancer development, including promoting cancer cell proliferation, migration, invasion, initiation, metabolic reprogramming, angiogenesis, and conferring drug resistance to cancer cells. Among these hotspot mutations, p53-R175H has the highest occurrence. Although losing the transactivating function of the wild-type p53 and prone to aggregation, p53-R175H gains oncogenic functions by interacting with many proteins. In this review, we summarize the gain of functions of p53-R175H in different cancer types, the interacting proteins of p53-R175H, and the downstream signaling pathways affected by p53-R175H to depict a comprehensive role of p53-R175H in cancer development. We also summarize treatments that target p53-R175H, including reactivating p53-R175H with small molecules that can bind to p53-R175H and alter it into a wild-type-like structure, promoting the degradation of p53-R175H by targeting heat-shock proteins that maintain the stability of p53-R175H, and developing immunotherapies that target the p53-R175H-HLA complex presented by tumor cells.

SUBMITTER: Chiang YT

PROVIDER: S-EPMC8391618 | biostudies-literature |

REPOSITORIES: biostudies-literature

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LncRNA H19 Promotes Lung Adenocarcinoma Progression via Binding to Mutant p53 R175H.

Project description:BackgroundAccumulating data suggest that long non-coding RNA (lncRNA) H19 and p53are closely related to the prognosis of lung cancer. This study aims to analyze the association and interaction betweenH19 and mutant p53 R175H in lung adenocarcinoma (LAC).MethodsMutant-type (Mt) p53 R175H was assessed by using RT-PCR in LAC cells and 100 cases of LAC tissue samples for association with H19 expression. Western blot, RNA-pull down, immunoprecipitation-Western blot and animal experiments were used to evaluate the interaction between H19 and mtp53.ResultsMtp53 R175H and H19 were over-expressed in LAC tissues and cells, while H19 over-expression extended the p53 half-life and enhanced transcriptional activity. Combined with anti-p53, ShH19 can significantly inhibit tumor growth in vivo.ConclusionsH19 over-expression may induce the elevated expression of mtp53 and interact with mtp53, leading to LAC progression. In addition, the high expression of mtp53 R175H is associated with poor overall survival inpatients. The simultaneous inhibition of H19 and mtp53 may provide a novel strategy for the effective control of LAC clinically.

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Human glioblastoma cells: Tet-on(mutant p53 R175H expression) vs Tet-off(p53-null)

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| S-ECPF-GEOD-33362 | biostudies-other

Mutant p53(R175H) upregulates Twist1 expression and promotes epithelial-mesenchymal transition in immortalized prostate cells.

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Human glioblastoma cells: Tet-on(mutant p53 R175H expression) vs Tet-off(p53-null)

2011-11-02 | GSE33362 | GEO

USP15-dependent lysosomal pathway controls p53-R175H turnover in ovarian cancer cells.

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Human glioblastoma cells: Tet-on(mutant p53 R175H expression) vs Tet-off(p53-null)

2011-11-02 | E-GEOD-33362 | biostudies-arrayexpress

Cytoplasmic gain-of-function mutant p53 contributes to inflammation-associated cancer.

Project description:Inflammation and mutation of the tumor suppressor p53 are two apparently unrelated conditions that are strongly associated with cancer initiation and progression. We recently reported that gain-of-function mutant p53 modifies the response of cancer cells to inflammatory signals by binding a cytoplasmic tumor suppressor protein involved in TNFα signaling.

| S-EPMC4905342 | biostudies-other

Pontin, a new mutant p53-binding protein, promotes gain-of-function of mutant p53.

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The gain of function of p53 cancer mutant in promoting mammary tumorigenesis.

Project description:Tumor suppressor p53 is critical for suppressing all types of human cancers, including breast cancer. The p53 gene is somatically mutated in over half of all human cancers. The majority of the p53 mutations are missense mutations, leading to the expression of the full-length p53 mutants. Several hotspot mutations, including R175H, are frequently detected in human breast cancer. P53 cancer mutants not only lose tumor suppression activity but, more problematically, also gain new oncogenic activities. Despite correlation of the expression of p53 cancer mutants and the poor prognosis of human breast cancer patients, the roles of p53 cancer mutants in promoting breast cancer remain unclear. We used the humanized p53 cancer mutant knock-in (R175H) mice and mouse mammary tumor virus (MMTV)-Wnt-1 transgenic (mWnt-1) mice to specifically address the gain of function of R175H in promoting breast cancer. Although both R175H/R175HmWnt-1(R175HmWnt-1) and p53(-/-)mWnt-1 mice died from mammary tumor at the same kinetics, which was much earlier than mWnt-1 mice, most of the R175HmWnt-1 mice developed multiple mammary tumors per mouse, whereas p53(-/-)mWnt-1 and mWnt-1 mice mostly developed one tumor per mouse. The multiple mammary tumors arose in the same R175HmWnt-1 mouse exhibited different histological characters. Moreover, R175H gain-of-function mutant expands the mammary epithelial stem cells (MESCs) that give rise to the mammary tumors. As ATM suppresses the expansion of MESCs, the inactivation of ATM by R175H in mammary epithelial cells (MECs) could contribute to the expansion of MESCs in R175HmWnt-1 mice. These findings provide the basis for R175H to promote the initiation of breast cancer by expanding MESCs.

| S-EPMC3586389 | biostudies-literature

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