Cyclin-dependent kinase 7 controls mRNA synthesis by affecting stability of preinitiation complexes, leading to altered gene expression, cell cycle progression, and survival of tumor cells
| Autor: | Karen Baumgart, Timothy W. R. Kelso, Bert Klebl, Claudia Antrecht, Sarah Lemcke, Jan Eickhoff, Michael Meisterernst, Thomas J. Albert |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
RNA polymerase II
Apoptosis Biology Cyclin-dependent kinase Cell Line Tumor Neoplasms Gene expression Roscovitine Humans RNA Messenger Phosphorylation Molecular Biology Protein Kinase Inhibitors Regulation of gene expression General transcription factor Dose-Response Relationship Drug Triazines Cell Cycle Cell Biology Articles Cell cycle Cyclin-Dependent Kinases Cell biology Gene Expression Regulation Neoplastic HEK293 Cells Pyrimidines Purines Transcription factor II H biology.protein Pyrazoles RNA Polymerase II Cyclin-dependent kinase 7 Cyclin-Dependent Kinase-Activating Kinase HeLa Cells |
| Zdroj: | Molecular and cellular biology. 34(19) |
| ISSN: | 1098-5549 |
| Popis: | Cyclin-dependent kinase 7 (CDK7) activates cell cycle CDKs and is a member of the general transcription factor TFIIH. Although there is substantial evidence for an active role of CDK7 in mRNA synthesis and associated processes, the degree of its influence on global and gene-specific transcription in mammalian species is unclear. In the current study, we utilize two novel inhibitors with high specificity for CDK7 to demonstrate a restricted but robust impact of CDK7 on gene transcription in vivo and in in vitro-reconstituted reactions. We distinguish between relative low- and high-dose responses and relate them to distinct molecular mechanisms and altered physiological responses. Low inhibitor doses cause rapid clearance of paused RNA polymerase II (RNAPII) molecules and sufficed to cause genome-wide alterations in gene expression, delays in cell cycle progression at both the G1/S and G2/M checkpoints, and diminished survival of human tumor cells. Higher doses and prolonged inhibition led to strong reductions in RNAPII carboxyl-terminal domain (CTD) phosphorylation, eventual activation of the p53 program, and increased cell death. Together, our data reason for a quantitative contribution of CDK7 to mRNA synthesis, which is critical for cellular homeostasis. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|