Inhibition of osteoclasts differentiation by CDC2-induced NFATc1 phosphorylation

被引:14
作者
Kim, Hye-Min [1 ]
He, Long [1 ,2 ]
Lee, Sangku [1 ]
Park, Chanmi [1 ]
Kim, Dong Hyun [1 ,5 ]
Han, Ho-Jin [1 ,5 ]
Han, Junyeol [1 ,5 ]
Hwang, Joonsung [1 ]
Cha-Molstad, Hyunjoo [1 ]
Lee, Kyung Ho [1 ]
Ko, Sung-Kyun [1 ]
Jang, Jae-Hyuk [1 ]
Ryoo, In-Ja [1 ]
Blenis, John [2 ]
Lee, Hee Gu [3 ]
Ahn, Jong Seog [1 ,5 ]
Kwon, Yong Tae [4 ]
Soung, Nak-Kyun [1 ,5 ]
Kim, Bo Yeon [1 ,5 ]
机构
[1] KRIBB, Anticanc Agent Res Ctr, Ochang 28116, Cheongju, South Korea
[2] Weill Cornell Med, Meyer Canc Ctr, New York, NY 10021 USA
[3] Korea Res Inst Biosci & Biotechnol, Immunotherapy Convergence Res Ctr, Daejeon 34141, South Korea
[4] Seoul Natl Univ, Coll Med, Dept Biomed Sci, Prot Metab Med Res Ctr, Seoul 03080, South Korea
[5] Univ Sci & Technol, Dept Biomol Sci, Daejeon 34113, South Korea
关键词
Ostecoclast; NFATc1; Cdc2; Zebrafish; ACTIVATED T-CELLS; NUCLEAR FACTOR; KINASE; BONE; CALCINEURIN; CANCER; CALCIUM; CDC2; IDENTIFICATION; REGULATORS;
D O I
10.1016/j.bone.2019.115153
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Bone homeostasis is regulated by a balance of bone formation and bone resorption; dysregulation of bone homeostasis may cause bone-related diseases (e.g., osteoporosis, osteopetrosis, bone fracture). Members of the nuclear factor of activated T cells (NFAT) family of transcription factors play crucial roles in the regulation of immune system, inflammatory responses, cardiac formation, skeletal muscle development, and bone homeostasis. Of these, NFATc1 is a key transcription factor mediating osteoclast differentiation, which is regulated by phosphorylation by distinct NFAT kinases including casein kinase 1 (CK1), glycogen synthase kinase 3 (GSK3), and dual-specificity tyrosine-phosphorylation-regulated kinases (DYRKs). In this study, we report that cell division control protein 2 homolog (cdc2) is a novel NFAT protein kinase that inhibits NFATc1 activation by direct phosphorylation of the NFATc1 S263 residue. Cdc2 inhibitors such as Roscovitine and BMI-1026 induce reduction of phosphorylation of NFATc1, and this process leads to the inhibition of NFATc1 translocation from the nucleus to the cytoplasm, consequently increasing the nuclear pool of NFATc1. Additionally, the inhibition of cdc2-mediated NFATc1 phosphorylation causes an elevation of osteoclast differentiation or TRAP-positive staining in zebrafish scales. Our results suggest that cdc2 is a novel NFAT protein kinase that negatively regulates osteoclast differentiation.
引用
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页数:11
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