Activation of the p53-MDM4 regulatory axis defines the anti-tumour response to PRMT5 inhibition through its role in regulating cellular splicing
| Autor: | Rocio Montes de Oca, Christopher L. Carpenter, Michael T. McCabe, Christine Thompson, Ann Boriack-Sjodin, Xi-Ping Zhang, Wendy A. Kellner, Kenneth W. Duncan, Melissa B. Pappalardi, Sarah Gerhart, Olena Barbash, Johnson Neil W, Ryan G. Kruger, BaoChau Le, Christina R. Majer, Elayne Penebre |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Gene isoform Protein-Arginine N-Methyltransferases Cell Survival RNA Splicing lcsh:Medicine Antineoplastic Agents Cell Cycle Proteins Arginine snRNP Core Proteins Article law.invention 03 medical and health sciences law Cell Line Tumor Proto-Oncogene Proteins Humans Protein Isoforms Enzyme Inhibitors lcsh:Science Loss function Multidisciplinary Chemistry Protein arginine methyltransferase 5 lcsh:R Cell Cycle Alternative splicing Nuclear Proteins Cell biology Alternative Splicing 030104 developmental biology Cell culture Cancer cell RNA splicing Suppressor lcsh:Q Tumor Suppressor Protein p53 |
| Zdroj: | Scientific Reports Scientific Reports, Vol 8, Iss 1, Pp 1-15 (2018) |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/s41598-018-28002-y |
| Popis: | Evasion of the potent tumour suppressor activity of p53 is one of the hurdles that must be overcome for cancer cells to escape normal regulation of cellular proliferation and survival. In addition to frequent loss of function mutations, p53 wild-type activity can also be suppressed post-translationally through several mechanisms, including the activity of PRMT5. Here we describe broad anti-proliferative activity of potent, selective, reversible inhibitors of protein arginine methyltransferase 5 (PRMT5) including GSK3326595 in human cancer cell lines representing both hematologic and solid malignancies. Interestingly, PRMT5 inhibition activates the p53 pathway via the induction of alternative splicing of MDM4. The MDM4 isoform switch and subsequent p53 activation are critical determinants of the response to PRMT5 inhibition suggesting that the integrity of the p53-MDM4 regulatory axis defines a subset of patients that could benefit from treatment with GSK3326595. |
| Databáze: | OpenAIRE |
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