The Establishment of a Hyperactive Structure Allows the Tumour Suppressor Protein p53 to Function through P-TEFb during Limited CDK9 Kinase Inhibition
| Autor: | Elisabeth Kremmer, Thomas K. Albert, Michael Meisterernst, Claudia Antrecht |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
Cyclin-Dependent Kinase Inhibitor p21
Transcriptional Activation 0301 basic medicine Chromatin Immunoprecipitation lcsh:Medicine RNA polymerase II Real-Time Polymerase Chain Reaction 03 medical and health sciences Transcription (biology) Cell Line Tumor Humans Positive Transcriptional Elongation Factor B RNA Small Interfering lcsh:Science Promoter Regions Genetic Enhancer P-TEFb Transcription factor Multidisciplinary Base Sequence biology Activator (genetics) lcsh:R Nuclear Proteins Cyclin-Dependent Kinase 9 Molecular biology Elongation factor HEK293 Cells 030104 developmental biology MCF-7 Cells biology.protein lcsh:Q RNA Interference Cyclin-dependent kinase 9 RNA Polymerase II Tumor Suppressor Protein p53 Sequence Alignment Research Article HeLa Cells Transcription Factors |
| Zdroj: | PLoS ONE PLoS ONE, Vol 11, Iss 1, p e0146648 (2016) PLoS ONE 11:e0146648 (2016) |
| ISSN: | 1932-6203 |
| DOI: | 10.1371/journal.pone.0146648 |
| Popis: | CDK9 is the catalytic subunit of positive elongation factor b (P-TEFb) that controls the transition of RNA polymerase II (RNAPII) into elongation. CDK9 inhibitors block mRNA synthesis and trigger activation of the stress-sensitive p53 protein. This in turn induces transcription of CDKN1A (p21) and other cell cycle control genes. It is presently unclear if and how p53 circumvents a general P-TEFb-requirement when it activates its target genes. Our investigations using a panel of specific inhibitors reason for a critical role of CDK9 also in the case of direct inhibition of the kinase. At the prototypic p21 gene, the activator p53 initially accumulates at the pre-bound upstream enhancer followed-with significant delay-by de novo binding to a secondary enhancer site within the first intron of p21. This is accompanied by recruitment of the RNAPII initiation machinery to both elements. ChIP and functional analyses reason for a prominent role of CDK9 itself and elongation factor complexes PAF1c and SEC involved in pause and elongation control. It appears that the strong activation potential of p53 facilitates gene activation in the situation of global repression of RNAPII transcription. The data further underline the fundamental importance of CDK9 for class II gene transcription. |
| Databáze: | OpenAIRE |
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