Targeting the Oncogenic p53 Mutants in Colorectal Cancer and Other Solid Tumors

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Colorectal cancer (CRC) is a kind of solid tumor and the third most common cancer type in the world. It is a heterogeneous disease characterized by genetic and epigenetic aberrations. The TP53 mutation is the key step driving the transition from adenoma to adenocarcinoma. The functional roles of TP53 mutation in tumor development have been comprehensively investigated. In CRC, TP53 mutation was associated with poor prognosis and chemoresistance. A gain of function (GOF) of p53 mutants promotes cell proliferation, migration and invasion through multiple mechanisms. Restoring wild type p53 function, depleting p53 mutants, or intervention by targeting the oncogenic downstreams provides potential therapeutic strategies. In this review, we comprehensively summarize the GOF of p53 mutants in CRC progression as well as in some other solid tumors, and discuss the current strategies targeting p53 mutants in malignancies.

Related collections

Most cited references 102

Record: found
Abstract: found
Article: not found

Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas.

Wen Xue, Lars Zender, Cornelius Miething … (2007)

Although cancer arises from a combination of mutations in oncogenes and tumour suppressor genes, the extent to which tumour suppressor gene loss is required for maintaining established tumours is poorly understood. p53 is an important tumour suppressor that acts to restrict proliferation in response to DNA damage or deregulation of mitogenic oncogenes, by leading to the induction of various cell cycle checkpoints, apoptosis or cellular senescence. Consequently, p53 mutations increase cell proliferation and survival, and in some settings promote genomic instability and resistance to certain chemotherapies. To determine the consequences of reactivating the p53 pathway in tumours, we used RNA interference (RNAi) to conditionally regulate endogenous p53 expression in a mosaic mouse model of liver carcinoma. We show that even brief reactivation of endogenous p53 in p53-deficient tumours can produce complete tumour regressions. The primary response to p53 was not apoptosis, but instead involved the induction of a cellular senescence program that was associated with differentiation and the upregulation of inflammatory cytokines. This program, although producing only cell cycle arrest in vitro, also triggered an innate immune response that targeted the tumour cells in vivo, thereby contributing to tumour clearance. Our study indicates that p53 loss can be required for the maintenance of aggressive carcinomas, and illustrates how the cellular senescence program can act together with the innate immune system to potently limit tumour growth.

0 comments Cited 784 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Mutant p53 gain of function in two mouse models of Li-Fraumeni syndrome.

Kenneth P Olive, David Tuveson, Zachary Ruhe … (2004)

The p53 tumor suppressor gene is commonly altered in human tumors, predominantly through missense mutations that result in accumulation of mutant p53 protein. These mutations may confer dominant-negative or gain-of-function properties to p53. To ascertain the physiological effects of p53 point mutation, the structural mutant p53R172H and the contact mutant p53R270H (codons 175 and 273 in humans) were engineered into the endogenous p53 locus in mice. p53R270H/+ and p53R172H/+ mice are models of Li-Fraumeni Syndrome; they developed allele-specific tumor spectra distinct from p53+/- mice. In addition, p53R270H/- and p53R172H/- mice developed novel tumors compared to p53-/- mice, including a variety of carcinomas and more frequent endothelial tumors. Dominant effects that varied by allele and function were observed in primary cells derived from p53R270H/+ and p53R172H/+ mice. These results demonstrate that point mutant p53 alleles expressed under physiological control have enhanced oncogenic potential beyond the simple loss of p53 function.

0 comments Cited 442 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis.

E Oda, R Ohki, H Murasawa … (2000)

A critical function of tumor suppressor p53 is the induction of apoptosis in cells exposed to noxious stresses. We report a previously unidentified pro-apoptotic gene, Noxa. Expression of Noxa induction in primary mouse cells exposed to x-ray irradiation was dependent on p53. Noxa encodes a Bcl-2 homology 3 (BH3)-only member of the Bcl-2 family of proteins; this member contains the BH3 region but not other BH domains. When ectopically expressed, Noxa underwent BH3 motif-dependent localization to mitochondria and interacted with anti-apoptotic Bcl-2 family members, resulting in the activation of caspase-9. We also demonstrate that blocking the endogenous Noxa induction results in the suppression of apoptosis. Noxa may thus represent a mediator of p53-dependent apoptosis.

0 comments Cited 402 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Journal

Journal ID (nlm-ta): Int J Mol Sci

Journal ID (iso-abbrev): Int J Mol Sci

Journal ID (publisher-id): ijms

Title: International Journal of Molecular Sciences

Publisher: MDPI

ISSN (Electronic): 1422-0067

Publication date (Electronic): 28 November 2019

Publication date Collection: December 2019

Volume: 20

Issue: 23

Electronic Location Identifier: 5999

Affiliations

[1 ]Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China; haifei616@ 123456163.com (H.L.); jinglinzhang@ 123456cuhk.edu.hk (J.Z.); jtong@ 123456cuhk.edu.hk (J.H.M.T.); awh_chan@ 123456cuhk.edu.hk (A.W.H.C.)

[2 ]Institute of Digestive Disease, State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China; junyu@ 123456cuhk.edu.hk

[3 ]Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, China

[4 ]Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China

Author notes

[* ]Correspondence: weikang@ 123456cuhk.edu.hk (W.K.); kfto@ 123456cuhk.edu.hk (K.F.T.); Tel.: +852-35051505 (W.K. & K.F.T.); Fax: +852-26497286 (W.K. & K.F.T.)

[†]

These authors contributed equally to this work.

Author information

Jinglin Zhang https://orcid.org/0000-0002-8254-8242

Wei Kang https://orcid.org/0000-0002-4651-677X

Article

Publisher ID: ijms-20-05999

DOI: 10.3390/ijms20235999

PMC ID: 6929124

PubMed ID: 31795192

SO-VID: 283e6a7e-53d3-4bed-90e6-62c3e46617c7

License:

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

Targeting the Oncogenic p53 Mutants in Colorectal Cancer and Other Solid Tumors

Read this article at

Abstract

Related collections

Karger: Oncology

Most cited references 102

Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas.

Mutant p53 gain of function in two mouse models of Li-Fraumeni syndrome.

Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis.

Author and article information

Journal

Affiliations

Author notes

Author information

Article

History

Categories

Comments

Comment on this article

Similar content 595

Cited by 41

Most referenced authors 2,010