Mutant p53 gains new function in promoting inflammatory signals by repression of the secreted interleukin-1 receptor antagonist

Ubertini, Valentina; Norelli, Giuseppe; D’Arcangelo, Daniela; Gurtner, Aymone; Cesareo, Eleonora; Baldari, Silvia; Gentileschi, Maria Pia; Piaggio, Giulia; Nisticò, Paola; Soddu, Silvia; Facchiano, Antonio; Bossi, Gianluca

doi:10.1038/onc.2014.191

Cited by 63 publications

(49 citation statements)

References 41 publications

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“…In another study, Bossi and colleagues revealed that both conformational and contact hotspot p53 mutants, R175H and R273H, respectively, were able to induce inflammatory signals by inhibiting the expression of a natural anti-inflammatory cytokine, the secreted interleukin-1 receptor antagonist (sIL-1Ra). This occurred through the protein-protein interaction between mutant p53 isoform and the transcriptional corepressor MAFF, and their binding to the sIL-1Ra promoter [165].…”

Section: Stimulation Of Pro-inflammatory Cytokinesmentioning

confidence: 99%

Mutant p53-Associated Molecular Mechanisms of ROS Regulation in Cancer Cells

et al. 2020

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The TP53 tumor suppressor gene is the most frequently altered gene in tumors and an increasing number of studies highlight that mutant p53 proteins can acquire oncogenic properties, referred to as gain-of-function (GOF). Reactive oxygen species (ROS) play critical roles as intracellular messengers, regulating numerous signaling pathways linked to metabolism and cell growth. Tumor cells frequently display higher ROS levels compared to healthy cells as a result of their increased metabolism as well as serving as an oncogenic agent because of its damaging and mutational properties. Several studies reported that in contrast with the wild type protein, mutant p53 isoforms fail to exert antioxidant activities and rather increase intracellular ROS, driving a pro-tumorigenic survival. These pro-oxidant oncogenic abilities of GOF mutant p53 include signaling and metabolic rewiring, as well as the modulation of critical ROS-related transcription factors and antioxidant systems, which lead ROS unbalance linked to tumor progression. The studies summarized here highlight that GOF mutant p53 isoforms might constitute major targets for selective therapeutic intervention against several types of tumors and that ROS enhancement driven by mutant p53 might represent an “Achilles heel” of cancer cells, suggesting pro-oxidant drugs as a therapeutic approach for cancer patients bearing the mutant TP53 gene.

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Section: Stimulation Of Pro-inflammatory Cytokinesmentioning

confidence: 99%

Mutant p53-Associated Molecular Mechanisms of ROS Regulation in Cancer Cells

et al. 2020

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“…Indeed, many hotspot mutations arm the mutant p53 with new weapons to promote cancer. Such activities, known as mutant p53 gain-of-function, are involved in regulation of various cancer hallmarks (Figure 3), including genomic instability [65–69], anti-apoptotic activities [70–79], replicative mortality [69, 80], invasion and metastasis [63, 64, 66, 67, 79, 81–91], angiogenesis [92–95], dysregulated metabolism [96–99], and tumor-related inflammation [100–103]. Mutant p53 gain-of-function can drive cancer through several potential mechanisms [104, 105]: (i) binding to structure-specific DNA to subsequently exert transcriptional regulation; (ii) interacting with transcription factors or cofactors to enhance or decease transcription of their targeted genes; (iii) associating with chromatin or the chromatin regulatory complex; and (iv) directly interacting with and influencing other proteins and their functions.…”

Section: Mutant P53 Gain-of-function: More Than Just a Lossmentioning

confidence: 99%

Li–Fraumeni Syndrome Disease Model: A Platform to Develop Precision Cancer Therapy Targeting Oncogenic p53

Zhou

Gingold

et al. 2017

Trends in Pharmacological Sciences

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Li-Fraumeni syndrome (LFS) is a rare hereditary autosomal dominant cancer disorder. Germ-line mutations in TP53 are responsible for most cases of LFS. p53 is also the most commonly mutated gene in human cancers. Because inhibition of mutant p53 is considered a promising therapeutic strategy to treat these diseases, LFS provides a perfect genetic model to study p53 mutation-associated malignancies as well as screen potential compounds targeting oncogenic p53. In this review, we will briefly summarize the biology of LFS and the current understanding of oncogenic functions of mutant p53 in cancer development. We will discuss the strengths and limitations of current LFS disease models and touch on existing compounds targeting oncogenic p53 and in vitro clinical trials to develop new ones. Finally, we discuss how recently developed methodologies can be integrated into the LFS iPSC platform to develop precision cancer therapy.

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“…mut p53, through prolonging of NF-κB activation and cell survival, can promote the inflammatory environment needed for the development of colorectal tumors. Ubertini et al (2015) [135] reported a novel mut p53 GOF in promoting inflammatory signals by the repression of the secreted interleukin-1 receptor antagonist (sIL-1Ra). The findings demonstrate that mut p53 tumorigenesis requires sIL-1Ra suppression, resulting in a chronic pro-inflammatory tumor microenvironment.…”

Section: Introductionmentioning

confidence: 99%

Emerging Non-Canonical Functions and Regulation by p53: p53 and Stemness

Olivos

Mayo

2016

IJMS

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Since its discovery nearly 40 years ago, p53 has ascended to the forefront of investigated genes and proteins across diverse research disciplines and is recognized most exclusively for its role in cancer as a tumor suppressor. Levine and Oren (2009) reviewed the evolution of p53 detailing the significant discoveries of each decade since its first report in 1979. In this review, we will highlight the emerging non-canonical functions and regulation of p53 in stem cells. We will focus on general themes shared among p53’s functions in non-malignant stem cells and cancer stem-like cells (CSCs) and the influence of p53 on the microenvironment and CSC niche. We will also examine p53 gain of function (GOF) roles in stemness. Mutant p53 (mutp53) GOFs that lead to survival, drug resistance and colonization are reviewed in the context of the acquisition of advantageous transformation processes, such as differentiation and dedifferentiation, epithelial-to-mesenchymal transition (EMT) and stem cell senescence and quiescence. Finally, we will conclude with therapeutic strategies that restore wild-type p53 (wtp53) function in cancer and CSCs, including RING finger E3 ligases and CSC maintenance. The mechanisms by which wtp53 and mutp53 influence stemness in non-malignant stem cells and CSCs or tumor-initiating cells (TICs) are poorly understood thus far. Further elucidation of p53’s effects on stemness could lead to novel therapeutic strategies in cancer research.

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Mutant p53 gains new function in promoting inflammatory signals by repression of the secreted interleukin-1 receptor antagonist

Cited by 63 publications

References 41 publications

Mutant p53-Associated Molecular Mechanisms of ROS Regulation in Cancer Cells

Mutant p53-Associated Molecular Mechanisms of ROS Regulation in Cancer Cells

Li–Fraumeni Syndrome Disease Model: A Platform to Develop Precision Cancer Therapy Targeting Oncogenic p53

Emerging Non-Canonical Functions and Regulation by p53: p53 and Stemness

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