A post-transcriptional program of chemoresistance by AU-rich elements and TTP in quiescent leukemic cells
| العنوان: | A post-transcriptional program of chemoresistance by AU-rich elements and TTP in quiescent leukemic cells |
|---|---|
| المؤلفون: | Benjamin Nicholson, Daniel A. Haber, David A. Sweetser, Shyamala Maheswaran, Min-Kyung Choo, Fei Ji, Douglas S. Micalizzi, Nicholas J. Haradhvala, Sooncheol Lee, Adam Langenbucher, Myriam Boukhali, Yasutaka Kato, David B. Sykes, Ruslan I. Sadreyev, Samuel S. Truesdell, Manuel D. Díaz-Muñoz, Roopali Gandhi, Syed I. A. Bukhari, Maria Antonietta Mazzola, Ipsita Dey-Guha, David T. Myers, Michael S. Lawrence, Dongjun Lee, Radhika Raheja, Shobha Vasudevan, Christopher Tiedje, Wilhelm Haas, Jennifer Lombardi-Story |
| المصدر: | Genome Biology, Vol 21, Iss 1, Pp 1-23 (2020) Genome Biology Lee, S, Micalizzi, D, Truesdell, S S, Bukhari, S I A, Boukhali, M, Lombardi-Story, J, Kato, Y, Choo, M K, Dey-Guha, I, Ji, F, Nicholson, B T, Myers, D T, Lee, D, Mazzola, M A, Raheja, R, Langenbucher, A, Haradhvala, N J, Lawrence, M S, Gandhi, R, Tiedje, C, Diaz-Muñoz, M D, Sweetser, D A, Sadreyev, R, Sykes, D, Haas, W, Haber, D A, Maheswaran, S & Vasudevan, S 2020, ' A post-transcriptional program of chemoresistance by AU-rich elements and TTP in quiescent leukemic cells ', Genome Biology, vol. 21, no. 1, 33 . https://doi.org/10.1186/s13059-020-1936-4Test |
| بيانات النشر: | BMC, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Proteome, THP-1 Cells, Cell, Quiescence, p38 Mitogen-Activated Protein Kinases, Transcriptome, Mice, 0302 clinical medicine, RNA Processing, Post-Transcriptional, lcsh:QH301-705.5, Cells, Cultured, 0303 health sciences, Post-transcriptional regulation, Cell Cycle, Intracellular Signaling Peptides and Proteins, Hep G2 Cells, 3. Good health, Leukemia, medicine.anatomical_structure, 030220 oncology & carcinogenesis, MCF-7 Cells, Signal transduction, Chemoresistance, TTP, lcsh:QH426-470, p38 mitogen-activated protein kinases, Protein Serine-Threonine Kinases, Biology, 03 medical and health sciences, Tristetraprolin, medicine, Animals, Humans, 030304 developmental biology, AU Rich Elements, AU-rich element, Tumor Necrosis Factor-alpha, Research, Dual Specificity Phosphatase 1, AU-rich elements, medicine.disease, Mice, Inbred C57BL, lcsh:Genetics, lcsh:Biology (General), Drug Resistance, Neoplasm, Cancer cell, Cancer research, K562 Cells |
| الوصف: | Background Quiescence (G0) is a transient, cell cycle-arrested state. By entering G0, cancer cells survive unfavorable conditions such as chemotherapy and cause relapse. While G0 cells have been studied at the transcriptome level, how post-transcriptional regulation contributes to their chemoresistance remains unknown. Results We induce chemoresistant and G0 leukemic cells by serum starvation or chemotherapy treatment. To study post-transcriptional regulation in G0 leukemic cells, we systematically analyzed their transcriptome, translatome, and proteome. We find that our resistant G0 cells recapitulate gene expression profiles of in vivo chemoresistant leukemic and G0 models. In G0 cells, canonical translation initiation is inhibited; yet we find that inflammatory genes are highly translated, indicating alternative post-transcriptional regulation. Importantly, AU-rich elements (AREs) are significantly enriched in the upregulated G0 translatome and transcriptome. Mechanistically, we find the stress-responsive p38 MAPK-MK2 signaling pathway stabilizes ARE mRNAs by phosphorylation and inactivation of mRNA decay factor, Tristetraprolin (TTP) in G0. This permits expression of ARE mRNAs that promote chemoresistance. Conversely, inhibition of TTP phosphorylation by p38 MAPK inhibitors and non-phosphorylatable TTP mutant decreases ARE-bearing TNFα and DUSP1 mRNAs and sensitizes leukemic cells to chemotherapy. Furthermore, co-inhibiting p38 MAPK and TNFα prior to or along with chemotherapy substantially reduces chemoresistance in primary leukemic cells ex vivo and in vivo. Conclusions These studies uncover post-transcriptional regulation underlying chemoresistance in leukemia. Our data reveal the p38 MAPK-MK2-TTP axis as a key regulator of expression of ARE-bearing mRNAs that promote chemoresistance. By disrupting this pathway, we develop an effective combination therapy against chemosurvival. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9c3d8a5697209272a49f2f869b19d3e0Test https://doaj.org/article/3a979733efdc48f9906f993aa9cadbcbTest |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....9c3d8a5697209272a49f2f869b19d3e0 |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |