Abstract
Ectopic expression of Wnt-1 in 3T3-L1 preadipocytes stabilizes beta-catenin, activates TCF-dependent gene transcription, and blocks adipogenesis. Here we report that upon serum withdrawal, Wnt-1 causes 3T3-L1 cells to resist apoptosis through a mechanism that is partially dependent on phosphatidylinositol 3-kinase. Although activation of Wnt signaling by inhibition of GSK-3 activity or ectopic expression of dominant stable beta-catenin blocks apoptosis, inhibition of Wnt signaling through expression of dominant negative TCF-4 increases apoptosis. Wnt-1 stimulates 3T3-L1 preadipocytes to secrete factors that increase PKB/Akt phosphorylation at levels comparable with treatment with 10% serum. With DNA microarrays, we identified several secreted antiapoptotic genes that are induced by Wnt-1, notably insulin-like growth factor I (IGF-I) and IGF-II. Consistent with IGFs mediating the antiapoptotic effects of Wnt-1 in preadipocytes, conditioned medium from Wnt-1 expressing 3T3-L1 cells was unable to promote protein kinase B phosphorylation after the addition of recombinant IGFBP-4. Thus, we demonstrated that Wnt-1 induces expression of antiapoptotic genes in 3T3-L1 preadipocytes such as IGF-I and IGF-II, which allows these cells to resist apoptosis in response to serum deprivation.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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3T3 Cells
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Adipocytes / drug effects
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Adipocytes / metabolism*
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Androstadienes / pharmacology
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Animals
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Apoptosis / physiology*
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Chromones / pharmacology
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Culture Media, Conditioned
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Culture Media, Serum-Free
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Cytoskeletal Proteins / genetics
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Cytoskeletal Proteins / metabolism
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Enzyme Inhibitors / pharmacology
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Humans
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Insulin-Like Growth Factor I / genetics
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Insulin-Like Growth Factor I / metabolism*
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Insulin-Like Growth Factor II / genetics
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Insulin-Like Growth Factor II / metabolism*
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Lithium / metabolism
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Mice
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Morpholines / pharmacology
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Oligonucleotide Array Sequence Analysis
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Phosphatidylinositol 3-Kinases / metabolism
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Protein Serine-Threonine Kinases*
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-akt
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Signal Transduction / physiology*
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Trans-Activators / genetics
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Trans-Activators / metabolism
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Wnt Proteins
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Wnt1 Protein
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Wortmannin
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Zebrafish Proteins*
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beta Catenin
Substances
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Androstadienes
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CTNNB1 protein, human
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CTNNB1 protein, mouse
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Chromones
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Culture Media, Conditioned
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Culture Media, Serum-Free
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Cytoskeletal Proteins
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Enzyme Inhibitors
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Morpholines
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Proto-Oncogene Proteins
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Trans-Activators
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WNT1 protein, human
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Wnt Proteins
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Wnt1 Protein
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Wnt1 protein, mouse
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Zebrafish Proteins
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beta Catenin
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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Insulin-Like Growth Factor I
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Insulin-Like Growth Factor II
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Lithium
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AKT1 protein, human
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Wortmannin