Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:B6E4X6 (mutant p53)
 3,342 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Li-Fraumeni syndrome (LFS) is a cancer predisposition disorder caused by germline mutations in TP53 that can lead to increased mitochondrial metabolism in patients. However, the implications of altered mitochondrial function for tumorigenesis in LFS are unclear. Here, we have reported that genetic or pharmacologic disruption of mitochondrial respiration improves cancer-free survival in a mouse model of LFS that expresses mutant p53. Mechanistically, inhibition of mitochondrial function increased autophagy and decreased the aberrant proliferation signaling caused by mutant p53. In a pilot study, LFS patients treated with metformin exhibited decreases in mitochondrial activity concomitant with activation of antiproliferation signaling, thus reproducing the effects of disrupting mitochondrial function observed in LFS mice. These observations indicate that a commonly prescribed diabetic medicine can restrain mitochondrial metabolism and tumorigenesis in an LFS model, supporting its further consideration for cancer prevention in LFS patients.
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PMID:Inhibiting mitochondrial respiration prevents cancer in a mouse model of Li-Fraumeni syndrome. 3122 6

p53 loss of heterozygosity (LOH) is a frequent event in tumors of somatic and Li-Fraumeni syndrome patients harboring p53 mutation. Here, we focused on resolving a possible crosstalk between the immune-system and p53 LOH. Previously, we reported that p53 heterozygous bone-marrow mesenchymal progenitor cells undergo p53 LOH in-vivo. Surprisingly, the loss of either the wild-type p53 allele or mutant p53 allele was detected with a three-to-one ratio in favor of losing the mutant allele. In this study, we examined whether the immune-system can affect the LOH directionality in bone marrow progenitors. We found that mesenchymal progenitor cells derived from immune-deficient mice exhibited the same preference of losing the mutant p53 allele as immune-competent matched cells, nevertheless, these animals showed a significantly shorter tumor-free survival, indicating the possible involvement of immune surveillance in this model. Surprisingly, spontaneous tumors of p53 heterozygous immune-deficient mice exhibited a significantly higher incidence of p53 LOH compared to that observed in tumors derived of p53 heterozygous immune-competent mice. These findings indicate that the immune-system may affect the p53 LOH prevalence in spontaneous tumors. Thus suggesting that the immune-system may recognize and clear cells that underwent p53 LOH, whereas in immune-compromised mice, those cells will form tumors with shorter latency. In individuals with a competent immune-system, p53 LOH independent pathways may induce malignant transformation which requires a longer tumor latency. Moreover, this data may imply that the current immunotherapy treatment aimed at abrogating the inhibition of cellular immune checkpoints may be beneficial for LFS patients.
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PMID:Immune deficiency augments the prevalence of p53 loss of heterozygosity in spontaneous tumors but not bi-directional loss of heterozygosity in bone marrow progenitors. 2800 5

Li-Fraumeni syndrome (LFS) is an autosomal dominant disorder where an oncogenic TP53 germline mutation is passed from parent to child. Tumor protein p53 is a key tumor suppressor regulating cell cycle arrest in response to DNA damage. Paradoxically, some mutant TP53 carriers remain unaffected, while their children develop cancer within the first few years of life. To address this paradox, response to UV stress was compared in dermal fibroblasts (dFb) from an affected LFS patient vs. their unaffected carrier parent. UV induction of CDKN1A/p21, a regulatory target of p53, in LFS patient dFb was significantly reduced compared to the unaffected parent. UV exposure also induced significantly greater p53[Ser15]-phosphorylation in LFS patient dFb, a reported property of some mutant p53 variants. Taken together, these results suggested that unaffected parental dFb may express an increased proportion of wild-type vs. mutant p53. Indeed, a significantly increased ratio of wild-type to mutant TP53 allele-specific expression in the unaffected parent dFb was confirmed by RT-PCR-RFLP and RNA-seq analysis. Hence, allele-specific expression of wild-type TP53 may allow an unaffected parent to mount a response to genotoxic stress more characteristic of homozygous wild-type TP53 individuals than their affected offspring, providing protection from the oncogenesis associated with LFS.
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PMID:Allele-specific wild-type TP53 expression in the unaffected carrier parent of children with Li-Fraumeni syndrome. 2827 9

Li-Fraumeni syndrome (LFS) is a rare hereditary autosomal dominant cancer disorder. Germline mutations in TP53, the gene encoding p53, are responsible for most cases of LFS. TP53 is also the most commonly mutated gene in human cancers. Because inhibition of mutant p53 is considered to be a promising therapeutic strategy to treat these diseases, LFS provides a perfect genetic model to study p53 mutation-associated malignancies as well as to screen potential compounds targeting oncogenic p53. In this review we briefly summarize the biology of LFS and current understanding of the oncogenic functions of mutant p53 in cancer development. We 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 induced pluripotent stem cell (iPSC) platform to develop precision cancer therapy.
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PMID:Li-Fraumeni Syndrome Disease Model: A Platform to Develop Precision Cancer Therapy Targeting Oncogenic p53. 2881 33

p53 is one of the most extensively studied proteins in cancer research. Mutations in p53 generally abolish normal p53 function, and some mutants can gain new oncogenic functions. However, the mechanisms underlying p53 mutation-driven cancer remains to be elucidated. Our study investigated the function of a heterozygous p53 mutation (p.Asn268Glufs*4) in a Li-Fraumeni syndrome (LFS) patient. We used episomal technology to perform somatic reprogramming, and used molecular and cell biology methods to determine the p53 mutation levels in patient-originated induced pluripotent stem (iPS) cells at the RNA and protein levels. We found that p53 protein expression was not increased in this patient's somatic cells compared with those of a healthy control. p53 mutation facilitates the proliferation of tumor cells by inhibiting apoptosis and promoting cell division. It can inhibit the efficiency of somatic reprogramming by inhibiting OCT4 expression during reprogramming stage. Moreover, not all p53 mutant iPS cell lines have mutant p53 RNA sequences. A small percentage of mutant p53 mRNA is present in the somatic cells from the patient and his mother. In summary, this p53 mutation can promote tumor cell proliferation, inhibit somatic reprogramming, and exhibit random p53 allelic expression of heterozygous mutations in the patient and iPS cells which may be one of the reasons why the people with p53 mutations develop cancer at random. This finding suggested that mutant p53 allelic expression should be added to the risk forecasting of cancer.
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PMID:The function of a heterozygous p53 mutation in a Li-Fraumeni syndrome patient. 3251 27


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