Abstract
Integrated pathways are believed to determine hematopoietic cell fate and/or neoplastic transformation. Notch signaling has been shown to regulate T-cell differentiation and leukemogenesis. However, specific target genes and molecular partners are not fully elucidated. We show that Notch3 activation sustains aberrant SCL/Tal1 overexpression and phosphorylation in mature thymocytes. Furthermore, we define the role of SCL/Tal1 as a component of an activator complex, including phosphorylated Tal1 and Sp1, that specifically enhances cyclin D1 expression and demonstrate that Tal1/Sp1 specifically co-occupy the D1 promoter in vivo, only in the presence of pre-T-cell receptor (TCR). We therefore conclude not only that cyclin D1 is a target of the Tal1/Sp1 complex, but also that Notch3-dependent activation of pre-TCR/ERK signaling regulates SCL/Tal1 function.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Basic Helix-Loop-Helix Transcription Factors / genetics*
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Basic Helix-Loop-Helix Transcription Factors / metabolism
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Cell Differentiation / genetics*
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Cell Transformation, Neoplastic / genetics*
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Cell Transformation, Neoplastic / metabolism
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Cyclin D1 / genetics
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Cyclin D1 / metabolism
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Extracellular Signal-Regulated MAP Kinases / genetics
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Gene Expression Regulation, Leukemic / genetics
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Humans
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Leukemia / genetics*
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Leukemia / metabolism
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Mice
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Mice, Mutant Strains
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Multiprotein Complexes / genetics
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Multiprotein Complexes / metabolism
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Neoplasm Proteins / genetics*
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Neoplasm Proteins / metabolism
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Promoter Regions, Genetic / genetics
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Proto-Oncogene Proteins / genetics*
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Proto-Oncogene Proteins / metabolism
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Receptor, Notch3
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Receptors, Antigen, T-Cell / genetics
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Receptors, Antigen, T-Cell / metabolism
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Receptors, Notch / genetics*
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Receptors, Notch / metabolism
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Signal Transduction / genetics*
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T-Cell Acute Lymphocytic Leukemia Protein 1
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T-Lymphocytes / metabolism
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T-Lymphocytes / pathology
Substances
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Basic Helix-Loop-Helix Transcription Factors
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Multiprotein Complexes
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Neoplasm Proteins
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Notch3 protein, mouse
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Proto-Oncogene Proteins
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Receptor, Notch3
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Receptors, Antigen, T-Cell
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Receptors, Notch
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T-Cell Acute Lymphocytic Leukemia Protein 1
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Tal1 protein, mouse
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Cyclin D1
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Extracellular Signal-Regulated MAP Kinases