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RANKL induces NFATc1 acetylation and stability via histone acetyltransferases during osteoclast differentiation
- Source :
- The Biochemical journal. 436(2)
- Publication Year :
- 2011
-
Abstract
- NFATc1 (nuclear factor of activated T-cells c1), a key transcription factor, plays a role in regulating expression of osteoclast-specific downstream target genes such as TRAP (tartrate-resistant acid phosphatase) and OSCAR (osteoclast-associated receptor). It has been shown that RANKL [receptor activator of NF-κB (nuclear factor κB) ligand] induces NFATc1 expression during osteoclastogenesis at a transcriptional level. In the present study, we demonstrate that RANKL increases NFATc1 protein levels by post-translational modification. RANKL stimulates NFATc1 acetylation via HATs (histone acetyltransferases), such as p300 and PCAF [p300/CREB (cAMP-response-element-binding protein)-binding protein-associated factor], thereby stabilizing NFATc1 proteins. PCAF physically interacts with NFATc1 and directly induces NFATc1 acetylation and stability, subsequently increasing the transcriptional activity of NFATc1. In addition, RANKL-mediated NFATc1 acetylation is increased by the HDAC (histone deacetylase) inhibitors sodium butyrate and scriptaid. Overexpression of HDAC5 reduces RANKL- or PCAF-mediated NFATc1 acetylation, stability and transactivation activity, suggesting that the balance between HAT and HDAC activities might play a role in the regulation of NFATc1 levels. Furthermore, RANKL and p300 induce PCAF acetylation and stability, thereby enhancing the transcriptional activity of NFATc1. Down-regulation of PCAF by siRNA (small interfering RNA) decreases NFATc1 acetylation and stability, as well as RANKL-induced osteoclastogenesis. Taken together, the results of the present study demonstrate that RANKL induces HAT-mediated NFATc1 acetylation and stability, and subsequently increases the transcriptional activity of NFATc1 during osteoclast differentiation.
- Subjects :
- musculoskeletal diseases
Osteoclasts
Biochemistry
chemistry.chemical_compound
Osteoclast
medicine
Humans
Molecular Biology
Cells, Cultured
Histone Acetyltransferases
Histone deacetylase 5
integumentary system
biology
NFATC Transcription Factors
Protein Stability
RANK Ligand
Sodium butyrate
Acetylation
Cell Differentiation
Cell Biology
Molecular biology
medicine.anatomical_structure
HEK293 Cells
chemistry
PCAF
RANKL
biology.protein
Histone deacetylase
Subjects
Details
- ISSN :
- 14708728
- Volume :
- 436
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- The Biochemical journal
- Accession number :
- edsair.doi.dedup.....49e53599bc9810d74b5507ffc6ad2816