Uncovering the role of p53 splice variants in human malignancy: a clinical perspective
TLDR
The understanding of the regulation of p53 isoform expression and their biological activities in relation to the cellular context would constitute an important step toward the improvement of the diagnostic, prognostic, and predictive values of p 53 in cancer treatment.Abstract:
Thirty-five years of research on p53 gave rise to more than 68,000 articles and reviews, but did not allow the uncovering of all the mysteries that this major tumor suppressor holds. How p53 handles the different signals to decide the appropriate cell fate in response to a stress and its implication in tumorigenesis and cancer progression remains unclear. Nevertheless, the uncovering of p53 isoforms has opened new perspectives in the cancer research field. Indeed, the human TP53 gene encodes not only one but at least twelve p53 protein isoforms, which are produced in normal tissues through alternative initiation of translation, usage of alternative promoters, and alternative splicing. In recent years, it became obvious that the different p53 isoforms play an important role in regulating cell fate in response to different stresses in normal cells by differentially regulating gene expression. In cancer cells, abnormal expression of p53 isoforms contributes actively to cancer formation and progression, regardless of TP53 mutation status. They can also be associated with response to treatment, depending on the cell context. The determination of p53 isoform expression and p53 mutation status helps to define different subtypes within a particular cancer type, which would have different responses to treatment. Thus, the understanding of the regulation of p53 isoform expression and their biological activities in relation to the cellular context would constitute an important step toward the improvement of the diagnostic, prognostic, and predictive values of p53 in cancer treatment. This review aims to summarize the involvement of p53 isoforms in cancer and to highlight novel potential therapeutic targets.read more
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Федеральное государственное бюджетное учреждение «Научно-исследовательский институт комплексных проблем сердечно-сосудистых заболеваний» Сибирского отделения Российской академии медицинских наук, Кемерово, Россия
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Induction of tumor apoptosis through a circular RNA enhancing Foxo3 activity
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Major apoptotic mechanisms and genes involved in apoptosis.
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Aberrant RNA splicing in cancer; expression changes and driver mutations of splicing factor genes
Anita Sveen,Anita Sveen,Sami Kilpinen,A Ruusulehto,Ragnhild A. Lothe,Ragnhild A. Lothe,Rolf Inge Skotheim,Rolf Inge Skotheim +7 more
TL;DR: This review provides an overview of aberrant RNA splicing and its regulation in cancer, and proposes 24 novel cancer-critical splicing factors predicted from somatic mutations.
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p53: 800 million years of evolution and 40 years of discovery
TL;DR: Why TP53 is the most commonly mutated gene in cancer is explored, discussing the evolutionary conservation of the p53 pathway in the context of tissue-specific functions and underlying reasons for the order of mutations which lead to p53-related cancer.
References
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p53 mutations in human cancers
TL;DR: The p53 mutational spectrum differs among cancers of the colon, lung, esophagus, breast, liver, brain, reticuloendothelial tissues, and hemopoietic tissues as mentioned in this paper.
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Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours
Lawrence A. Donehower,Michele Harvey,Betty L. Slagle,Mark J. McArthur,Charles A. Montgomery,Janet S. Butel,Allan Bradley +6 more
TL;DR: Observations indicate that a normal p53 gene is dispensable for embryonic development, that its absence predisposes the animal to neoplastic disease, and that an oncogenic mutant form of p53 is not obligatory for the genesis of many types of tumours.
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In vivo activation of the p53 pathway by small-molecule antagonists of MDM2.
Lyubomir T. Vassilev,Binh Thanh Vu,Bradford Graves,Daisy Carvajal,Frank John Podlaski,Zoran Filipovic,Norman Kong,Ursula Kammlott,Christine Lukacs,Christian Klein,Nader Fotouhi,Liu Emily Aijun +11 more
TL;DR: In this article, the authors identify potent and selective small-molecule antagonists of MDM2 and confirm their mode of action through the crystal structures of complexes, leading to cell cycle arrest, apoptosis, and growth inhibition of human tumor xenografts.
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The p53 tumour suppressor gene
TL;DR: The cell cycle is composed of a series of steps which can be negatively or postively regulated by various factors, chief among the negative regulators is the p53 protein, which can lead to cancer.
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Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms
David Malkin,Frederick P. Li,Frederick P. Li,Louise C. Strong,Joseph F. Fraumeni,Camille E. Nelson,Camille E. Nelson,David H. Kim,Jayne Kassel,Magdalena A. Gryka,Farideh Z. Bischoff,Michael A. Tainsky,Stephen H. Friend +12 more
TL;DR: Germ line p53 mutations have been detected in all five LFS families analyzed and can now be examined in additional families with LFS, and in other cancer patients and families with clinical features that might be attributed to the mutation.