Histone deacetylase inhibition-mediated post-translational elevation of p27KIP1 protein levels is required for G1 arrest in fibroblasts
| Autor: | Douglas V. Faller, James S. Chen |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
BALB 3T3 Cells
Cyclin E Physiology Clinical Biochemistry Cell Cycle Proteins Butyrate Hydroxamic Acids Histone Deacetylases Mice CDC2-CDC28 Kinases medicine Animals Enzyme Inhibitors Feedback Physiological Histone deacetylase 5 biology Kinase HDAC11 Tumor Suppressor Proteins Cyclin-Dependent Kinase 2 Cyclin-dependent kinase 2 G1 Phase Cell Biology Fibroblasts Molecular biology Up-Regulation Histone Deacetylase Inhibitors Butyrates Trichostatin A NIH 3T3 Cells biology.protein Histone deacetylase Protein Processing Post-Translational Cyclin-Dependent Kinase Inhibitor p27 medicine.drug |
| Zdroj: | Journal of Cellular Physiology. 202:87-99 |
| ISSN: | 1097-4652 0021-9541 |
| Popis: | Butyrate, a non-toxic short-chain fatty acid (SCFA) and inhibitor of histone deacetylase (HDAC), has potential as an anti-tumor agent because it imposes a reversible G 1 block in normal cells yet induces apoptosis in tumor lines. As a potent reactivator of fetal globin transcription, butyrate is used clinically in the treatment of hemoglobinopathies. The anti-proliferative effect of butyrate and its derivatives on in vivo erythroid cell maturation, however, has limited their utility. The molecular mechanisms underlying the G 1 arrest induced by butyrate and related SCFAs remain unclear. One model, drawing on tumor cell data, proposes that HDAC inhibition and subsequent transcriptional induction of cyclin-dependent kinase inhibitor (CKI) p21 C I P are required. However, because of potentially confounding genetic mutations present in tumor models, we examined SCFA effects on CKIs in a non-transformed growth control model. Using murine 3T3 fibroblasts, we find p27 K I P 1 is also strongly induced. Unlike previously described effects of butyrate and HDAC inhibition on p21 C I P , p27 K I P 1 induction did not occur at the transcriptional level; instead, the stability of the p27 K I P 1 protein increased. Other structurally unrelated HDAC inhibitors, including trichostatin A (TSA), induced p27 K I P 1 similarly. p27 K I P 1 was found in cyclin E/Cdk2 complexes, concomitant with suppression of cdk2 activity. Elevation of p27 K I P 1 is required for the observed G 1 blockade, as p27 K I P 1 -deficient fibroblasts were resistant to HDAC inhibition-induced arrest. These data suggest a novel activity for HDAC inhibitors and demonstrate a critical role for p27 K I P 1 in mediating G 1 arrest in response to these drugs. |
| Databáze: | OpenAIRE |
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