Abstract
The tumor suppressor PTEN is altered in many cancers, including breast cancer, but only a handful of factors are known to control its expression. PTEN plays a vital role in cell survival and proliferation by regulating Akt phosphorylation, a key component of the phosphatidylinositol 3 kinase (PI3K) pathway. Here we show that insulin-like growth factor-II (IGF-II), which signals through PI3K, regulates PTEN expression in the mammary gland. IGF-II injection into mouse mammary gland significantly increased PTEN expression. Transgenic IGF-II expression also increased mammary PTEN protein, leading to reductions in Akt phosphorylation, epithelial proliferation, and mammary morphogenesis. IGF-II induced PTEN promoter activity and protein levels and this involved the immediate early gene egr-1. Thus, we have identified a novel negative feedback loop within the PI3K pathway where IGF-II induces PTEN expression to modulate its physiologic effects.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Blotting, Western
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Cell Division
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Cell Survival
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DNA-Binding Proteins / metabolism
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Dose-Response Relationship, Drug
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Early Growth Response Protein 1
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Epithelial Cells / metabolism
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Feedback, Physiological
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Gene Expression Regulation*
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Immediate-Early Proteins*
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Insulin-Like Growth Factor II / metabolism
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Insulin-Like Growth Factor II / physiology*
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Luciferases / metabolism
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Mammary Glands, Animal / metabolism*
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Mice
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Mice, Transgenic
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PTEN Phosphohydrolase
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoric Monoester Hydrolases / biosynthesis*
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Phosphoric Monoester Hydrolases / genetics
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Phosphorylation
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Promoter Regions, Genetic
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Reverse Transcriptase Polymerase Chain Reaction
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Time Factors
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Transcription Factors / metabolism
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Transfection
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Transgenes
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Tumor Suppressor Proteins / biosynthesis*
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Tumor Suppressor Proteins / genetics
Substances
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DNA-Binding Proteins
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Early Growth Response Protein 1
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Egr1 protein, mouse
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Immediate-Early Proteins
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Transcription Factors
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Tumor Suppressor Proteins
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Insulin-Like Growth Factor II
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Luciferases
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Phosphatidylinositol 3-Kinases
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Phosphoric Monoester Hydrolases
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PTEN Phosphohydrolase