The specific roles of mutant p53's dominant-negative (DN) or gain-of-function (GOF) properties in regulating acute response and long-term tumorigenesis is unclear. Using "knockin" mouse strains expressing varying R246S mutant levels, we show that the DN effect on transactivation is universally observed after acute p53 activation, whereas the effect on cellular outcome is cell-type specific. Reducing mutant p53 levels abrogated the DN effect. Mutant p53's DN effect protected against radiation-induced death but did not accentuate tumorigenesis. Furthermore, the R246S mutant did not promote tumorigenesis compared to p53(-/-) mice in various models, even when MDM2 is absent, unlike the R172H mutant. Together, these data demonstrate that mutant p53's DN property only affects acute responses, whereas GOF is not universal, being mutation-type specific.
Download full-text PDF |
Source |
---|---|
http://dx.doi.org/10.1016/j.ccr.2012.10.022 | DOI Listing |
Cell Commun Signal
October 2024
Cancer Biology Lab, Department of Bioresources, School of Biological Sciences, University of Kashmir Srinagar, Kashmir Srinagar, J&K, 190006, India.
The p53 mutation is the most common genetic mutation associated with human neoplasia. TP53 missense mutations, which frequently arise early in breast cancer, are present in over thirty percent of breast tumors. In breast cancer, p53 mutations are linked to a more aggressive course of the disease and worse overall survival rates.
View Article and Find Full Text PDFGenomics Proteomics Bioinformatics
December 2024
Division of Computational Biology, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA.
An accurate assessment of p53's functional statuses is critical for cancer genomic medicine. However, there is a significant challenge in identifying tumors with non-mutational p53 inactivation which is not detectable through DNA sequencing. These undetected cases are often misclassified as p53-normal, leading to inaccurate prognosis and downstream association analyses.
View Article and Find Full Text PDFNat Commun
September 2024
Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
Proteins
February 2025
Department of Chemistry, Delaware State University, Dover, Delaware, USA.
Considering p53's pivotal role as a tumor suppressor protein, proactive identification and characterization of potentially harmful p53 mutations are crucial before they appear in the population. To address this, four computational prediction tools-SIFT, Polyphen-2, PhD-SNP, and MutPred2-utilizing sequence-based and machine-learning algorithms, were employed to identify potentially deleterious p53 nsSNPs (nonsynonymous single nucleotide polymorphisms) that may impact p53 structure, dynamics, and binding with DNA. These computational methods identified three variants, namely, C141Y, C238S, and L265P, as detrimental to p53 stability.
View Article and Find Full Text PDFNat Rev Clin Oncol
February 2024
Karolinska Institutet, Department of Oncology-Pathology, Stockholm, Sweden.
p53, which is encoded by the most frequently mutated gene in cancer, TP53, is an attractive target for novel cancer therapies. Despite major challenges associated with this approach, several compounds that either augment the activity of wild-type p53 or restore all, or some, of the wild-type functions to p53 mutants are currently being explored. In wild-type TP53 cancer cells, p53 function is often abrogated by overexpression of the negative regulator MDM2, and agents that disrupt p53-MDM2 binding can trigger a robust p53 response, albeit potentially with induction of p53 activity in non-malignant cells.
View Article and Find Full Text PDFEnter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!