title: RANKL induces NFATc1 acetylation and stability via histone acetyltransferases during osteoclast differentiation.
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.
authors.affiliation: National Research Laboratory for Regulation of Bone Metabolism and Disease, Medical Research Center for Gene Regulation, Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju 501-746, South Korea.
authors.forename: Jung Ha
authors.initials: JH
authors.lastname: Kim
authors.forename: Kabsun
authors.initials: K
authors.lastname: Kim
authors.forename: Bang Ung
authors.initials: BU
authors.lastname: Youn
authors.forename: Hye Mi
authors.initials: HM
authors.lastname: Jin
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Kim
authors.forename: Jang Bae
authors.initials: JB
authors.lastname: Moon
authors.forename: Aeran
authors.initials: A
authors.lastname: Ko
authors.forename: Sang-Beom
authors.initials: SB
authors.lastname: Seo
authors.forename: Kwang-Youl
authors.initials: KY
authors.lastname: Lee
authors.forename: Nacksung
authors.initials: N
authors.lastname: Kim
mesh_terms: D000107:Acetylation; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D057809:HEK293 Cells; D051548:Histone Acetyltransferases / Q000378:metabolism*; D006801:Humans; D050778:NFATC Transcription Factors / Q000378:metabolism*; D010010:Osteoclasts / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism*; D055550:Protein Stability; D053245:RANK Ligand / Q000502:physiology*
chemical_list: D050778:NFATC Transcription Factors; C494003:NFATC1 protein, human; D053245:RANK Ligand; D051548:Histone Acetyltransferases