Abstract
Cytokines, such as tumor necrosis factor-alpha (TNFalpha), potently inhibit the differentiation of mesenchymal cells and down-regulate the expression of Sox9 and MyoD, transcription factors required for chondrocyte and myocyte development. Previously, we demonstrated that NF-kappaB controls TNFalpha-mediated suppression of myogenesis through a mechanism involving MyoD mRNA down-regulation. Here, we show that NF-kappaB also suppresses chondrogenesis and destabilizes Sox9 mRNA levels. Multiple copies of an mRNA cis-regulatory motif (5'-ACUACAG-3') are necessary and sufficient for NF-kappaB-mediated Sox9 and MyoD down-regulation. Thus, in response to cytokine signaling, NF-kappaB modulates the differentiation of mesenchymal-derived cell lineages via RNA sequence-dependent, posttranscriptional down-regulation of key developmental regulators.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Base Sequence
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Cell Differentiation / physiology*
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Cells, Cultured
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Chondrocytes / cytology
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Chondrocytes / physiology
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Conserved Sequence
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Down-Regulation
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High Mobility Group Proteins / genetics
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High Mobility Group Proteins / metabolism
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Mesoderm / cytology*
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Mesoderm / metabolism
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Mice
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MyoD Protein / genetics
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MyoD Protein / metabolism
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Myoblasts / cytology
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Myoblasts / metabolism
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NF-kappa B / genetics
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NF-kappa B / metabolism*
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RNA Interference*
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RNA, Messenger / metabolism
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Regulatory Sequences, Nucleic Acid
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SOX9 Transcription Factor
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Signal Transduction
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Transcription Factors / genetics
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Transcription Factors / metabolism
Substances
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High Mobility Group Proteins
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MyoD Protein
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NF-kappa B
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RNA, Messenger
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SOX9 Transcription Factor
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Sox9 protein, mouse
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Transcription Factors