Cyclin-dependent kinases 7 and 9 specifically regulate neutrophil transcription and their inhibition drives apoptosis to promote resolution of inflammation
| Autor: | Andrew E. Leitch, John A. Marwick, Rodger Duffin, Adriano G. Rossi, Christopher D. Lucas, Christopher Haslett |
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| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
DOWN-REGULATION
Transcription Genetic Neutrophils LIPOPOLYSACCHARIDE 0302 clinical medicine AGING NEUTROPHILS Phosphorylation MACROPHAGES P-TEFb 0303 health sciences biology Kinase apoptosis neutrophil Hep G2 Cells Cyclin-Dependent Kinases 3. Good health Cell biology cyclin-dependent kinase 030220 oncology & carcinogenesis RNA Polymerase II Programmed cell death RNA-POLYMERASE-II HL-60 Cells 03 medical and health sciences Cyclin-dependent kinase Roscovitine Humans Protein Kinase Inhibitors Molecular Biology 030304 developmental biology Inflammation Original Paper INTERFERON-GAMMA resolution IN-VITRO Cell Biology Cyclin-Dependent Kinase 9 P-TEFB CELL-DEATH Purines Apoptosis inflammation biology.protein Cyclin-dependent kinase 9 Cyclin-dependent kinase 7 MCL-1 Dichlororibofuranosylbenzimidazole Cyclin-Dependent Kinase-Activating Kinase CDK inhibitor |
| Zdroj: | Leitch, A E, Lucas, C, Marwick, J A, Duffin, R, Haslett, C & Rossi, A G 2012, ' Cyclin-dependent kinases 7 and 9 specifically regulate neutrophil transcription and their inhibition drives apoptosis to promote resolution of inflammation ', Cell Death and Differentiation, vol. 19, no. 12, pp. 1950-1961 . https://doi.org/10.1038/cdd.2012.80 Cell Death and Differentiation |
| DOI: | 10.1038/cdd.2012.80 |
| Popis: | Terminally differentiated neutrophils are short-lived but the key effector cells of the innate immune response, and have a prominent role in the pathogenesis and propagation of many inflammatory diseases. Delayed apoptosis, which is responsible for their extended longevity, is critically dependent on a balance of intracellular survival versus pro-apoptotic proteins. Here, we elucidate the mechanism by which the cyclin-dependent kinase (CDK) inhibitor drugs such as R-roscovitine and DRB (5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole) mediate neutrophil apoptosis. We demonstrate (by a combination of microarray, confocal microscopy, apoptosis assays and western blotting) that the phosphorylation of RNA polymerase II by CDKs 7 and 9 is inhibited by R-roscovitine and that specific effects on neutrophil transcriptional capacity are responsible for neutrophil apoptosis. Finally, we show that specific CDK7 and 9 inhibition with DRB drives resolution of neutrophil-dominant inflammation. Thus, we highlight a novel mechanism that controls both primary human neutrophil transcription and apoptosis that could be targeted by selective CDK inhibitor drugs to resolve established inflammation.Cell Death and Differentiation advance online publication, 29 June 2012; doi:10.1038/cdd.2012.80. |
| Databáze: | OpenAIRE |
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