Kim JH, Kim K, Youn BU, Jin HM, Kim JY, Moon JB, Ko A, Seo SB, Lee KY, Kim N

NFATc1, a key transcription factor, plays a role in regulating expression of osteoclast-specific downstream target genes such as TRAP and OSCAR. It has been shown that RANKL induces NFATc1 expression during osteoclastogenesis at a transcriptional level. Herein, we demonstrate that RANKL increases NFATc1 protein levels by post-translational modification. RANKL stimulates ...

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NFATc1 acetylation via histone acetyltransferases (HATs) such as p300 and p300/CREB binding protein-associated factor (PCAF), 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 histone deacetylase (HDAC) 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. Downregulation of PCAF by siRNA decreases NFATc1 acetylation and stability, as well as RANKL-induced osteoclastogenesis. Taken together, our data demonstrate that RANKL induces HAT-mediated NFATc1 acetylation and stability, and subsequently increases the transcriptional activity of NFATc1 during osteoclast differentiation.

Date: Mar. 18, 2011

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