Abstract
To evaluate the role of murine TFIID subunit TAF4 in activation of cellular genes by all-trans retinoic acid (T-RA), we have characterized the T-RA response of taf4(lox/-) and taf4(-/-) embryonic fibroblasts. T-RA regulates almost 1000 genes in taf4(lox/-) cells, but less than 300 in taf4(-/-) cells showing that TAF4 is required for T-RA regulation of most, but not all cellular genes. We further show that T-RA-treated taf4(lox/-) cells exhibit transforming growth factor (TGF)beta-dependent autocrine growth and identify a set of genes regulated by loss of TAF4 and by T-RA corresponding to key mediators of the TGFbeta signalling pathway. T-RA rapidly and potently induces expression of connective tissue growth factor (CTGF) via a conserved DR2 type response element in its proximal promoter leading to serum-free autocrine growth. These results highlight the role of TAF4 as a cofactor in the cellular response to T-RA and identify the genetic programme of a novel cross talk between the T-RA and TGFbeta pathways that leads to deregulated cell growth.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Autocrine Communication / drug effects*
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Autocrine Communication / genetics
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Base Sequence
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COS Cells
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Cell Proliferation / drug effects*
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Cells, Cultured
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Chlorocebus aethiops
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Connective Tissue Growth Factor
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Consensus Sequence
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Fibroblasts / drug effects*
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Fibroblasts / physiology*
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Gene Expression Profiling
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Gene Expression Regulation / drug effects
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Immediate-Early Proteins / genetics
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Intercellular Signaling Peptides and Proteins / genetics
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Mice
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Receptor Cross-Talk / drug effects
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Receptors, Retinoic Acid / metabolism
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Response Elements
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Retinoic Acid Receptor gamma
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Transcription Factor TFIID / genetics
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Transcription Factor TFIID / metabolism
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Transcription Factor TFIID / physiology
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Transforming Growth Factor beta / genetics
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Transforming Growth Factor beta / physiology*
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Tretinoin / pharmacology*
Substances
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CCN2 protein, mouse
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Immediate-Early Proteins
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Intercellular Signaling Peptides and Proteins
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Receptors, Retinoic Acid
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TAF4 protein, mouse
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Transcription Factor TFIID
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Transforming Growth Factor beta
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Connective Tissue Growth Factor
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Tretinoin