Abstract
Liver kinase b1 (Lkb1) protein kinase activity regulates cell growth and cell polarity. Here, we show Lkb1 is essential for maintaining a balance between mitotic and postmitotic cell fates in development of the mammalian skeleton. In this process, Lkb1 activity controls the progression of mitotic chondrocytes to a mature, postmitotic hypertrophic fate. Loss of this Lkb1-dependent switch leads to a dramatic expansion of immature chondrocytes and formation of enchondroma-like tumors. Pathway analysis points to a mammalian target of rapamycin complex 1-dependent mechanism that can be partially suppressed by rapamycin treatment. These findings highlight a critical requirement for integration of mammalian target of rapamycin activity into developmental decision-making during mammalian skeletogenesis.
Keywords:
cell death; chondrocyte differentiation; endochondral ossification; hypoxia.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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AMP-Activated Protein Kinases
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Analysis of Variance
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Animals
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Bromodeoxyuridine
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Cell Differentiation / physiology*
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Chondrocytes / cytology*
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Histological Techniques
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In Situ Hybridization
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Mechanistic Target of Rapamycin Complex 1
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Mice
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Multiprotein Complexes / antagonists & inhibitors
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Multiprotein Complexes / metabolism
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Phenylurea Compounds
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Protein Serine-Threonine Kinases / metabolism*
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Signal Transduction / physiology*
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Sirolimus / pharmacology
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TOR Serine-Threonine Kinases / antagonists & inhibitors
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TOR Serine-Threonine Kinases / metabolism
Substances
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Multiprotein Complexes
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Phenylurea Compounds
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ethylene diurea
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Mechanistic Target of Rapamycin Complex 1
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Protein Serine-Threonine Kinases
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Stk11 protein, mouse
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TOR Serine-Threonine Kinases
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AMP-Activated Protein Kinases
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Bromodeoxyuridine
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Sirolimus