Developmentally regulated inhibition of cell cycle progression by glucocorticoids through repression of cyclin A transcription in primary osteoblast cultures
| Autor: | Tommy Noh, Baruch Frenkel, Yankel Gabet, Christopher Lee |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
endocrine system
medicine.medical_specialty Transcription Genetic Physiology Cyclin D Clinical Biochemistry Cyclin A Cyclin B Dexamethasone Proto-Oncogene Proteins c-myc Mice Cyclin D1 Internal medicine polycyclic compounds medicine Animals Cell Lineage RNA Messenger Promoter Regions Genetic Psychological repression Glucocorticoids Cells Cultured Osteoblasts biology ATF4 Cell Cycle Wnt signaling pathway Gene Expression Regulation Developmental Osteoblast Cell Biology Activating Transcription Factor 4 Cell biology Wnt Proteins medicine.anatomical_structure Endocrinology Animals Newborn biology.protein hormones hormone substitutes and hormone antagonists Signal Transduction |
| Zdroj: | Journal of cellular physiology. 226(4) |
| ISSN: | 1097-4652 |
| Popis: | Synthetic glucocorticoids (GCs) like dexamethasone (DEX) are effective immunosuppressants indicated for autoimmune and inflammatory diseases. However, they often promote osteoporosis and bone fractures. Here, we investigated the anti-mitogenic effect of GCs in primary osteoblast cultures. DEX did not affect cell cycle progression in confluent (day 2), or early post-confluent cultures. Starting on day 5, however, DEX strongly inhibited the G1/S cell cycle transition. Day 5 also marked the beginning of a ∼2-day commitment stage, during which cultures acquired resistance to the inhibitory effect of DEX on mineralization. Considering the importance of Wnt signaling in osteoblast development, we analyzed the effect of DEX on the Wnt pathway. DEX treatment did not inhibit the TOPGAL Wnt reporter before, but only during and after the commitment stage. However, this inhibition was not associated with repression of neither cyclin D1 nor c-Myc mRNA, well-established Wnt targets regulating cell cycle progression. On the other hand, acute (24-h) and chronic (7 days) DEX treatment significantly reduced both the mRNA and protein levels of cyclin A, another cell cycle regulator. Moreover, cyclin A repression by DEX was not observed before, but only during and after the commitment stage. Using gel shift and reporter assays, we identified an ATF/CREB-binding site critical for the DEX-mediated repression of cyclin A transcription. Furthermore, and similar to cyclin A, Atf4 expression was repressed by DEX only during and after commitment. Our data suggest that GCs attenuate cell cycle progression in osteoblasts in a developmental stage-specific manner by repressing Atf4-dependent cyclin A gene expression. |
| Databáze: | OpenAIRE |
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