The p53 protein induces stable miRNAs that have the potential to modify subsequent p53 responses
| Autor: | Erin J. Vanzyl, Miguel A. Cabrita, Reetesh Bose, Bruce C. McKay, Kristen A. Marcellus, Elysia Pan, Alyssa Pastic, Jeff D. Hamill |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Transcriptional Activation RNA Stability Biology law.invention 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation law Cell Line Tumor Neoplasms microRNA Genetics Humans RNA Messenger Transcription factor Messenger RNA BTG2 Gene Expression Profiling General Medicine Microarray Analysis Molecular biology Reverse transcription polymerase chain reaction Gene Expression Regulation Neoplastic MicroRNAs 030104 developmental biology 030220 oncology & carcinogenesis biology.protein Suppressor Mdm2 Tumor Suppressor Protein p53 HT29 Cells |
| Zdroj: | Gene. 608 |
| ISSN: | 1879-0038 |
| Popis: | The p53 tumour suppressor is a transcription factor that can increase the expression of mRNAs and microRNAs (miRNAs). HT29-tsp53 cells expressing a temperature sensitive variant of p53 have provided a useful model to rapidly and reversibly control p53 activity. In this model, the majority of p53-responsive mRNAs were upregulated rapidly but they were short-lived leading to rapid decay of the p53 response at the restrictive temperature. Here we used oligonucleotide microarrays and reverse transcriptase PCR to show that p53-induced miRNAs exhibited a distinct temporal pattern of expression. Whereas p53-induced miRNAs like miR-143-3p, miR-145-5p, miR-34a-5p and miR-139-5p increased as fast as mRNAs, they were extremely stable persisting long after p53 induced mRNAs and even their corresponding primary miRNAs had decayed to baseline levels. Three p53-induced mRNAs (MDM2, BTG2 and CDKN1A) are experimentally verified targets of one or more of these specific miRNAs so we hypothesized that the sustained expression of p53-induced miRNAs could be explained by a post-transcriptional feedback loop. Activation of consecutive p53 responses separated by a period of recovery led to the selective attenuation of a subset of p53 regulated mRNAs corresponding to those targeted by one or more of the p53-responsive miRNAs. Our results indicate that the long term expression of p53 responsive miRNAs leads to an excess of miRNAs during the second response and this likely prevents the induction of MDM2, BTG2 and CDKN1A mRNA and/or protein. These observations are likely to have important implications for daily cancer therapies that activate p53 in normal tissues and/or tumour cells. |
| Databáze: | OpenAIRE |
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