The tumour suppressor p53 is frequently mutated in tumours. Mutant p53 (Mutp53) proteins often gain new activities in promoting tumorigenesis, defined as gain-of-function (GOF). Mutp53 can accumulate to high levels in tumours, which promotes mutp53 GOF in tumorigenesis. The mechanism of mutp53 accumulation is poorly understood. Here we find that MDM2 isoforms promote mutp53 accumulation in tumours. MDM2 isoform B (MDM2-B), the MDM2 isoform most frequently over-expressed in human tumours, interacts with full-length MDM2 to inhibit MDM2-mediated mutp53 degradation, promoting mutp53 accumulation and GOF in tumorigenesis. Furthermore, MDM2-B overexpression correlates with mutp53 accumulation in human tumours. In mutp53 knock-in mice, a MDM2 isoform similar to human MDM2-B is overexpressed in the majority of tumours, which promotes mutp53 accumulation and tumorigenesis. Thus, overexpression of MDM2 isoforms promotes mutp53 accumulation in tumours, contributing to mutp53 GOF in tumorigenesis. This may be an important mechanism by which MDM2 isoforms promote tumorigenesis.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3960723 | PMC |
| http://dx.doi.org/10.1038/ncomms3996 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Oncogenic HJURP enhancer promotes the aggressive behavior of triple-negative breast cancer in association with p53/E2F1/FOXM1-axis.
Cancer Lett
December 2024
Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China. Electronic address:
Triple-negative breast cancer (TNBC) represents the most aggressive subtype of breast cancer, lacking effective targeted therapies and presenting with a poor prognosis. In this study, we utilized the epigenomic landscape, TCGA database, and clinical samples to uncover the pivotal role of HJURP in TNBC. Our investigation revealed a strong correlation between elevated HJURP expression and unfavorable prognosis, metastatic progression, and late-stage of breast cancer.
View Article and Find Full Text PDFA Fungicide, Fludioxonil, Formed the Polyploid Giant Cancer Cells and Induced Metastasis and Stemness in MDA-MB-231 Triple-Negative Breast Cancer Cells.
Int J Mol Sci
August 2024
Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju 28644, Chungbuk, Republic of Korea.
Fludioxonil, an antifungal agent used as a pesticide, leaves a measurable residue in fruits and vegetables. It has been identified to cause endocrine disruption, interrupt normal development, and cause various diseases such as cancers. In this study, fludioxonil was examined for its effects on the development and metastasis of breast cancer cells.
View Article and Find Full Text PDFWild-type and mutant p53 in cancer-related ferroptosis. A matter of stress management?
Front Genet
March 2023
Department of Life Sciences, University of Trieste, Trieste, Italy.
Cancer cells within tumor masses are chronically exposed to stress caused by nutrient deprivation, oxygen limitation, and high metabolic demand. They also accumulate hundreds of mutations, potentially generating aberrant proteins that can induce proteotoxic stress. Finally, cancer cells are exposed to various damages during chemotherapy.
View Article and Find Full Text PDFThe ubiquitin ligase TRIM21 regulates mutant p53 accumulation and gain of function in cancer.
J Clin Invest
March 2023
Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, New Jersey, USA.
The tumor suppressor TP53 is the most frequently mutated gene in human cancers. Mutant p53 (mutp53) proteins often accumulate to very high levels in human cancers to promote cancer progression through the gain-of-function (GOF) mechanism. Currently, the mechanism underlying mutp53 accumulation and GOF is incompletely understood.
View Article and Find Full Text PDFMutant p53 in cancer: from molecular mechanism to therapeutic modulation.
Cell Death Dis
November 2022
Bio-Medical Research Center, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, 730000, China.
TP53, a crucial tumor suppressor gene, is the most commonly mutated gene in human cancers. Aside from losing its tumor suppressor function, mutant p53 (mutp53) often acquires inherent, novel oncogenic functions, which is termed "gain-of-function". Emerging evidence suggests that mutp53 is highly associated with advanced malignancies and poor prognosis, which makes it a target for development of novel cancer therapies.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!