Should mutant TP53 be targeted for cancer therapy?
- Author(s)
- Wang, Z; Strasser, A; Kelly, GL;
- Journal Title
- Cell Death and Differentiation
- Publication Type
- epub ahead of print
- Abstract
- Mutations in the TP53 tumour suppressor gene are found in ~50% of human cancers [1-6]. TP53 functions as a transcription factor that directly regulates the expression of ~500 genes, some of them involved in cell cycle arrest/cell senescence, apoptotic cell death or DNA damage repair, i.e. the cellular responses that together prevent tumorigenesis [1-6]. Defects in TP53 function not only cause tumour development but also impair the response of malignant cells to anti-cancer drugs, particularly those that induce DNA damage [1-6]. Most mutations in TP53 in human cancers cause a single amino acid substitution, usually within the DNA binding domain of the TP53 protein. These mutant TP53 proteins are often expressed at high levels in the malignant cells. Three cancer causing attributes have been postulated for mutant TP53 proteins: the inability to activate target genes controlled by wt TP53 (loss-of-function, LOF) that are critical for tumour suppression, dominant negative effects (DNE), i.e. blocking the function of wt TP53 in cells during early stages of transformation when mutant and wt TP53 proteins are co-expressed, and gain-of-function (GOF) effects whereby mutant TP53 impacts diverse cellular pathways by interacting with proteins that are not normally engaged by wt TP53 [1-6]. The GOF effects of mutant TP53 were reported to be essential for the sustained proliferation and survival of malignant cells and it was therefore proposed that agents that can remove mutant TP53 protein would have substantial therapeutic impact [7-9]. In this review article we discuss evidence for and against the value of targeting mutant TP53 protein for cancer therapy.
- Publisher
- NPG
- Research Division(s)
- Blood Cells And Blood Cancer
- PubMed ID
- 35332311
- Publisher's Version
- https://doi.org/10.1038/s41418-022-00962-9
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2022-04-08 10:53:30
Last Modified: 2022-04-08 11:20:01