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Potential therapeutic targets of TP53 gene in the context of its classically canonical functions and its latest non-canonical functions in human cancer

Toshimichi Tanaka, Masahiko Watanabe _ and Keishi Yamashita

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Oncotarget. 2018; 9:16234-16247. https://doi.org/10.18632/oncotarget.24611

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Abstract

Toshimichi Tanaka1, Masahiko Watanabe1 and Keishi Yamashita1,2

1Department of Surgery, Kitasato University School of Medicine, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan

2Division of Advanced Surgical Oncology, Department of Research and Development Center for New Medical Frontiers, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan

Correspondence to:

Keishi Yamashita, email: keishi23@med.kitasato-u.ac.jp

Keywords: p53; mutation; gain of function; non-canonical function; carcinogenesis

Received: February 10, 2017    Accepted: February 10, 2018    Published: March 23, 2018

ABSTRACT

In normal tissue, p53 protein has a wide range of functions involving cell homeostasis; its mutation, however, permits a carcinogenic acquisition of function. TP53 gene mutation is a major genomic aberration in various human cancers and is a critical event in the multi-step carcinogenesis process. TP53 mutation is clinically relevant for the molecular classification of carcinogenesis, as most recently described rigorously by the Cancer Genome Atlas Research Network. TP53 gene mutation has been considered to work as a tumor suppressor gene through the loss of its transcriptional activity, which is designated as a canonical function. However, in cancer patients with mutant TP53, mutated p53 protein is frequently overexpressed, suggesting the activation of an oncogenic process through a gain of function (GOF). As part of this GOF, molecular mechanisms explaining the non-canonical function of TP53 gene abnormality have been reported, in which mutant p53 unconventionally binds with various critical molecules suppressing oncogenic properties, such as p63 and p73. Moreover, mutant TP53 gene-targeted therapy has been rigorously developed, and promising clinical trials have been started. In this study, we summarize the novel aspects of mutant p53 and describe its prominent therapeutic potentials in human cancer.


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