Abstract
Cripto-1 (CR-1), a member of the epidermal growth factor-CFC peptide family, activates the ras/raf/mitogen-activated protein/extracellular signal-regulated kinase/mitogen-activated protein kinase pathway. In the present study, the role of CR-1 in the phosphatidylinositol 3'-kinase (PI3K)/AKT (protein kinase B)/glycogen synthase kinase 3beta (GSK-3beta)-dependent signaling pathway was evaluated in human SiHa cervical carcinoma cells. Our data demonstrate that CR-1 can enhance the tyrosine phosphorylation of the p85 regulatory subunit of PI3K and transiently induce the phosphorylation of AKT in a time- and dose-dependent manner. In addition, CR-1 was found to induce the phosphorylation of GSK-3beta. Phosphorylation of AKT and GSK-3beta by CR-1 can be blocked by LY294002, a specific inhibitor of PI3K, thus leading to apoptosis. Finally, the apoptotic effect of LY294002 can be partially rescued by exogenous CR-1. In summary, our data suggest that human CR-1 may function as a survival factor through a PI3K-dependent signaling pathway involving AKT and GSK-3beta.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
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Chromones / pharmacology
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Culture Media, Serum-Free
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Enzyme Inhibitors / pharmacology
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Epidermal Growth Factor*
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Female
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GPI-Linked Proteins
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Glycogen Synthase Kinase 3
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Glycogen Synthase Kinases
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Growth Substances / physiology
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Humans
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Intercellular Signaling Peptides and Proteins
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Membrane Glycoproteins*
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Morpholines / pharmacology
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Neoplasm Proteins / physiology*
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Phosphatidylinositol 3-Kinases / metabolism*
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Phosphorylation
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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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Recombinant Proteins / metabolism
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Transfection
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Tumor Cells, Cultured
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Uterine Cervical Neoplasms
Substances
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Chromones
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Culture Media, Serum-Free
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Enzyme Inhibitors
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GPI-Linked Proteins
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Growth Substances
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Intercellular Signaling Peptides and Proteins
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Membrane Glycoproteins
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Morpholines
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Neoplasm Proteins
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Proto-Oncogene Proteins
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Recombinant Proteins
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TDGF1 protein, human
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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Epidermal Growth Factor
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Glycogen Synthase Kinases
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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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Calcium-Calmodulin-Dependent Protein Kinases
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Glycogen Synthase Kinase 3