RRC ID 62263
Author Yan B, Zhang Z, Jin D, Cai C, Jia C, Liu W, Wang T, Li S, Zhang H, Huang B, Lai P, Wang H, Liu A, Zeng C, Cai D, Jiang Y, Bai X.
Title mTORC1 regulates PTHrP to coordinate chondrocyte growth, proliferation and differentiation.
Journal Nat Commun
Abstract Precise coordination of cell growth, proliferation and differentiation is essential for the development of multicellular organisms. Here, we report that although the mechanistic target of rapamycin complex 1 (mTORC1) activity is required for chondrocyte growth and proliferation, its inactivation is essential for chondrocyte differentiation. Hyperactivation of mTORC1 via TSC1 gene deletion in chondrocytes causes uncoupling of the normal proliferation and differentiation programme within the growth plate, resulting in uncontrolled cell proliferation, and blockage of differentiation and chondrodysplasia in mice. Rapamycin promotes chondrocyte differentiation and restores these defects in mutant mice. Mechanistically, mTORC1 downstream kinase S6K1 interacts with and phosphorylates Gli2, and releases Gli2 from SuFu binding, resulting in nuclear translocation of Gli2 and transcription of parathyroid hormone-related peptide (PTHrP), a key regulator of bone development. Our findings demonstrate that dynamically controlled mTORC1 activity is crucial to coordinate chondrocyte proliferation and differentiation partially through regulating Gli2/PTHrP during endochondral bone development.
Volume 7
Pages 11151
Published 2016-4-4
DOI 10.1038/ncomms11151
PII ncomms11151
PMID 27039827
PMC PMC4822018
MeSH Animals Cell Differentiation Cell Enlargement Cell Proliferation Chondrocytes / cytology* Mechanistic Target of Rapamycin Complex 1 Mice Multiprotein Complexes / genetics Multiprotein Complexes / metabolism Multiprotein Complexes / physiology* Parathyroid Hormone-Related Protein / genetics Parathyroid Hormone-Related Protein / metabolism Parathyroid Hormone-Related Protein / physiology* Phosphorylation TOR Serine-Threonine Kinases / genetics TOR Serine-Threonine Kinases / metabolism TOR Serine-Threonine Kinases / physiology* Tuberous Sclerosis Complex 1 Protein Tumor Suppressor Proteins / genetics
IF 12.121
Human and Animal Cells ATDC5(RCB0565)