Details
- Autor(en) / Beteiligte
- Titel
- Tristetraprolin regulates cyclin D1 and c-Myc mRNA stability in response to rapamycin in an Akt-dependent manner via p38 MAPK signaling
- Ist Teil von
- Oncogene, 2006-10, Vol.25 (47), p.6277-6290
- Ort / Verlag
- Basingstoke: Nature Publishing
- Erscheinungsjahr
- 2006
- Link zum Volltext
- Quelle
- EZB-FREE-00999 freely available EZB journals
- Beschreibungen/Notizen
- The differential expression of the critical cell cycle control proteins cyclin D1 and c-myc has been shown to result in Akt-dependent hypersensitivity of tumor cells to mTOR inhibitors. We have previously demonstrated that the differential utilization of internal ribosome entry sites within the mRNAs of these transcripts allows maintenance of protein synthesis in the face of rapamycin (rapa) exposure in an Akt-dependent manner. Here, we demonstrate that in addition to this mechanism, cyclin D1 and c-myc mRNA stability is also coordinately regulated following rapa treatment depending on Akt activity status. We identify A/U-rich response elements within the 3' untranslated regions (UTRs) of these transcripts, which confer the observed differential stabilities and show that the RNA-binding protein, tristetraprolin (TTP), interacts with these elements. We also present evidence that TTP accumulates in response to rapa exposure, binds to the cis-acting elements within the cyclin D1 and c-myc 3' UTRs and is differentially serine phosphorylated in an Akt-dependent manner. Furthermore, the differential phosphorylation status of TTP results in its sequestration by 14-3-3 proteins in quiescent Akt-containing cells. Finally, siRNA-mediated knockdown of TTP expression or inhibiting a known regulator of TTP phosphorylation, p38 MAP kinase, abolishes the effects on cyclin D1 and c-myc mRNA stability. We assume that the differential control of cyclin D1 and c-myc mRNA stability and translational efficiency constitutes a coordinate response to rapa contributing to the maintenance of expression of these determinants in rapa-resistant quiescent Akt-containing cells following exposure.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0950-9232eISSN: 1476-5594DOI: 10.1038/sj.onc.1209645Titel-ID: cdi_proquest_miscellaneous_68949831
- Format
- –
- Schlagworte
- 14-3-3 protein, 14-3-3 Proteins - metabolism, 3' Untranslated regions, AKT protein, Animals, Binding sites, Biological and medical sciences, c-Myc protein, Cell cycle, Cell Line - drug effects, Cell Line - metabolism, Cell physiology, Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes, Cyclin D, Cyclin D1, Cyclins - genetics, Dactinomycin - pharmacology, Embryo, Mammalian, Fibroblasts - drug effects, Fibroblasts - metabolism, Fundamental and applied biological sciences. Psychology, Genes, bcl-1, Genes, myc, Genes, Reporter, Half-Life, Hypersensitivity, Imidazoles - pharmacology, Kinases, MAP kinase, Mice, Molecular and cellular biology, mRNA stability, Myc protein, p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors, p38 Mitogen-Activated Protein Kinases - physiology, Phosphorylation, Phosphoserine - metabolism, Protein Binding - drug effects, Protein biosynthesis, Protein Processing, Post-Translational, Protein Synthesis Inhibitors - pharmacology, Proteins, Proto-Oncogene Proteins c-akt - physiology, PTEN Phosphohydrolase - deficiency, PTEN Phosphohydrolase - physiology, Pyridines - pharmacology, Rapamycin, Recombinant Fusion Proteins - metabolism, Regulatory sequences, Regulatory Sequences, Nucleic Acid, Ribonucleic acid, Ribosomes - metabolism, RNA, RNA Interference, RNA, Messenger - metabolism, RNA, Small Interfering - pharmacology, RNA-binding protein, Signal transduction, siRNA, Sirolimus - pharmacology, TOR protein, Tristetraprolin - chemistry, Tristetraprolin - physiology, Tumor cells