Abstract
We analyzed the G-actin-regulated transcriptome by gene expression analysis using previously characterized actin-binding drugs. We found many known MAL/MRTF-dependent target genes of serum response factor (SRF), as well as additional directly regulated genes. Surprisingly, several putative antiproliferative target genes were identified, including mig6/errfi-1, a negative regulator of the EGFR family. Mig6 induction occurred through actin-MAL-SRF signaling, and MAL was inducibly recruited to and activated a mig6 promoter element. Upregulation of Mig6 by lipid agonists such as LPA and S1P or actin drugs involved MAL and correlated with decreased activation of EGFR, MAPK/Erk, and c-fos. Mig6 depletion restored EGFR signaling and provided a proliferative advantage. Overexpression of MAL exhibited strong antiproliferative effects requiring the domains for SRF binding and transactivation, which supports antagonistic functions of MAL on growth-promoting signals. Our results show the existence of negatively acting transcriptional networks between pro- and antiproliferative signaling pathways toward SRF.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Actins / physiology*
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Adaptor Proteins, Signal Transducing / physiology*
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Animals
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Bridged Bicyclo Compounds, Heterocyclic / pharmacology
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Cell Line
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Cell Proliferation
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Cycloheximide / pharmacology
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Cytochalasin D / pharmacology
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ErbB Receptors / metabolism*
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Gene Expression Profiling
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Gene Expression Regulation
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Humans
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Intracellular Signaling Peptides and Proteins
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Ligands
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MAP Kinase Signaling System* / drug effects
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Membrane Transport Proteins / physiology*
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Mice
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Myelin Proteins / physiology*
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Myelin and Lymphocyte-Associated Proteolipid Proteins
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Nucleic Acid Synthesis Inhibitors / pharmacology
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Proteolipids / physiology*
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RNA, Messenger / metabolism
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Thiazolidines / pharmacology
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Tumor Suppressor Proteins
Substances
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Actins
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Adaptor Proteins, Signal Transducing
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Bridged Bicyclo Compounds, Heterocyclic
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ERRFI1 protein, human
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Errfi1 protein, mouse
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Intracellular Signaling Peptides and Proteins
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Ligands
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MAL protein, human
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Mal protein, mouse
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Membrane Transport Proteins
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Myelin Proteins
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Myelin and Lymphocyte-Associated Proteolipid Proteins
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Nucleic Acid Synthesis Inhibitors
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Proteolipids
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RNA, Messenger
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Thiazolidines
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Tumor Suppressor Proteins
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Cytochalasin D
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Cycloheximide
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ErbB Receptors
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latrunculin B