Abstract
The Smad family proteins are critical components of the transforming growth factor (TGF)-beta signaling pathway. TGF-beta is a multipotent cytokine that elicits many biological functions. In particular, TGF-beta exhibits effects on the cell cycle manifested by G1-phase arrest, differentiation, or apoptosis of several target cells, suggesting that disruption of TGF-beta signaling pathway could be involved in cancer formation. Here we show one missense mutation of the Smad4 gene in the MH1 domain (P102L) and one frame shift mutation resulting in termination in the MH2 domain (Delta(483 - 552)) in acute myelogeneous leukemia. Both of the mutated Smad4 proteins lack transcriptional activities. Concomitant expression of the P102L mutant with wild-type Smad4 inactivates wild-type Smad4 through inhibiting its DNA-binding ability. The Delta(483 - 552) mutant blocks nuclear translocation of wild-type Smad4 and thus disrupts TGF-beta signaling. This is the first report showing that mutations in the Smad4 gene are associated with the pathogenesis of acute myelogeneous leukemia and the obtained results should provide useful insights into the mechanism whereby disruption of TGF-beta signaling pathway could lead to acute myelogeneous leukemia. Oncogene (2001) 20, 88 - 96.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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COS Cells
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Cell Division / genetics
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Cell Transformation, Neoplastic / genetics
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Cell Transformation, Neoplastic / metabolism
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Cell Transformation, Neoplastic / pathology
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DNA / metabolism
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DNA-Binding Proteins / antagonists & inhibitors
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DNA-Binding Proteins / biosynthesis
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DNA-Binding Proteins / genetics*
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DNA-Binding Proteins / metabolism
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DNA-Binding Proteins / physiology
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Enzyme Activation / genetics
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Gene Expression Regulation, Neoplastic
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Genes, Tumor Suppressor / physiology*
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Genetic Vectors / metabolism
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Growth Inhibitors / antagonists & inhibitors
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Growth Inhibitors / physiology
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HL-60 Cells
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Humans
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Jurkat Cells
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Leukemia, Myeloid, Acute / genetics*
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Leukemia, Myeloid, Acute / metabolism
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Leukemia, Myeloid, Acute / pathology
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Mutation*
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Plasminogen Activator Inhibitor 1 / metabolism
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Promoter Regions, Genetic / genetics
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Protein Binding / genetics
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Recombinant Fusion Proteins / biosynthesis
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Serine Proteinase Inhibitors / pharmacology
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Signal Transduction / genetics*
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Smad3 Protein
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Smad4 Protein
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Subcellular Fractions / metabolism
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Trans-Activators / antagonists & inhibitors
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Trans-Activators / biosynthesis
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Trans-Activators / genetics*
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Trans-Activators / metabolism
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Trans-Activators / physiology
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Transcriptional Activation / genetics
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Transforming Growth Factor beta / antagonists & inhibitors
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Transforming Growth Factor beta / physiology
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Tumor Cells, Cultured
Substances
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DNA-Binding Proteins
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Growth Inhibitors
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Plasminogen Activator Inhibitor 1
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Recombinant Fusion Proteins
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SMAD3 protein, human
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SMAD4 protein, human
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Serine Proteinase Inhibitors
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Smad3 Protein
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Smad4 Protein
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Trans-Activators
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Transforming Growth Factor beta
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DNA