Abstract
The T-cell leukemia/lymphoma 1 (TCL1) oncogene is a target of chromosomal translocations and inversions at 14q31.2, and its rearrangement in T cells causes T-cell prolymphocytic leukemias. TCL1 dysregulation in B cells is responsible for the development of an aggressive form of chronic lymphocytic leukemia (CLL), the most common human leukemia. We have investigated the mechanisms underlying the oncogenic functions of Tcl1 protein using a mass spectrometry approach and have identified Atm (ataxia-telangiectasia mutated) as a candidate Tcl1-interacting protein. The Tcl1-Atm complex formation was validated by coimmunoprecipitation experiments. Importantly, we show that the association of Atm with Tcl1 leads to enhanced IκBα phosphorylation and ubiquitination and subsequent activation of the NF-κB pathway. Our findings reveal functional cross-talk between Atm and Tcl1 and provide evidence for a novel pathway that could be targeted in leukemias and lymphomas.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Ataxia Telangiectasia Mutated Proteins
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Blotting, Western
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism*
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Cell Proliferation
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Female
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Humans
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I-kappa B Proteins / metabolism
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Immunoprecipitation
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Leukemia, B-Cell / genetics
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Leukemia, B-Cell / metabolism*
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Leukemia, Lymphocytic, Chronic, B-Cell / genetics
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Leukemia, Lymphocytic, Chronic, B-Cell / metabolism*
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Luciferases / metabolism
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Mice
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Mice, Nude
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Mice, Transgenic
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NF-KappaB Inhibitor alpha
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NF-kappa B / genetics
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NF-kappa B / metabolism*
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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RNA, Messenger / genetics
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Real-Time Polymerase Chain Reaction
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Reverse Transcriptase Polymerase Chain Reaction
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Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism*
Substances
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Cell Cycle Proteins
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DNA-Binding Proteins
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I-kappa B Proteins
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NF-kappa B
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NFKBIA protein, human
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Nfkbia protein, mouse
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Proto-Oncogene Proteins
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RNA, Messenger
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TCL1A protein, human
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Tumor Suppressor Proteins
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NF-KappaB Inhibitor alpha
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Luciferases
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ATM protein, human
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Ataxia Telangiectasia Mutated Proteins
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Atm protein, mouse
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Protein Serine-Threonine Kinases