RRC ID 51726
著者 Shang X, Wang J, Luo Z, Wang Y, Morandi MM, Marymont JV, Hilton MJ, Dong Y.
タイトル Notch signaling indirectly promotes chondrocyte hypertrophy via regulation of BMP signaling and cell cycle arrest.
ジャーナル Sci Rep
Abstract Cell cycle regulation is critical for chondrocyte differentiation and hypertrophy. Recently we identified the Notch signaling pathway as an important regulator of chondrocyte proliferation and differentiation during mouse cartilage development. To investigate the underlying mechanisms, we assessed the role for Notch signaling regulation of the cell cycle during chondrocyte differentiation. Real-time RT-PCR data showed that over-expression of the Notch Intracellular Domain (NICD) significantly induced the expression of p57, a cell cycle inhibitor, in chondrocytes. Flow cytometric analyses further confirmed that over-expression of NICD in chondrocytes enhances the G0/G1 cell cycle transition and cell cycle arrest. In contrast, treatment of chondrocytes with the Notch inhibitor, DAPT, decreased both endogenous and BMP2-induced SMAD 1/5/8 phosphorylation and knockdown of SMAD 1/5/8 impaired NICD-induced chondrocyte differentiation and p57 expression. Co-immunoprecipitation using p-SMAD 1/5/8 and NICD antibodies further showed a strong interaction of these proteins during chondrocyte maturation. Finally, RT-PCR and Western blot results revealed a significant reduction in the expression of the SMAD-related phosphatase, PPM1A, following NICD over-expression. Taken together, our results demonstrate that Notch signaling induces cell cycle arrest and thereby initiates chondrocyte hypertrophy via BMP/SMAD-mediated up-regulation of p57.
巻・号 6
ページ 25594
公開日 2016-5-5
DOI 10.1038/srep25594
PII srep25594
PMID 27146698
PMC PMC4857138
MeSH Animals Bone Morphogenetic Protein 2 / genetics* Bone Morphogenetic Protein 2 / metabolism Cell Cycle Checkpoints / genetics* Cell Differentiation / genetics Cell Enlargement Cell Line, Tumor Cell Proliferation / genetics Chondrocytes / metabolism* Chondrocytes / pathology Cyclin-Dependent Kinase Inhibitor p57 / genetics Cyclin-Dependent Kinase Inhibitor p57 / metabolism Gene Expression Regulation Mice Phosphorylation RNA Interference Receptors, Notch / genetics* Receptors, Notch / metabolism Signal Transduction / genetics Smad Proteins, Receptor-Regulated / genetics Smad Proteins, Receptor-Regulated / metabolism
IF 3.998
引用数 10
リソース情報
ヒト・動物細胞 ATDC5(RCB0565)