p53 deficiency and misexpression of protein kinase CK2alpha collaborate in the development of thymic lymphomas in mice.
Protein kinase CK2 (casein kinase II) is a serine-threonine protein kinase with many substrates, some of which are involved in cell cycle regulation. CK2 activity is elevated in human solid tumors and leukemia, and dysregulated expression of CK2 induces lymphoma in transgenic mice. Mice that are deficient in p53 also develop lymphomas, and p53 activity may be regulated by CK2 phosphorylation. Here we demonstrate that CK2alpha transgenic mice partially or completely deficient in p53 develop thymic lymphomas at a markedly accelerated rate when compared to p53-deficient mice lacking the transgene. Lymphomas originating from CK2alpha transgenic mice that are heterozygous for p53 generally lose the wild type p53 allele, indicating that loss of p53 is an important step in tumor progression. Moreover, though lymphomas occur as early as 3 weeks of age in the transgenic mice that are nullizygous for p53, they are still monoclonal, indicating that additional stochastic mutations are required for their development. These lymphomas express high levels of myc mRNA and frequently ectopically express Lmo-2, a transcription factor involved in human T cell acute lymphocytic leukemia. The p53-null CK2alpha transgenic lymphomas grow rapidly but are highly prone to apoptosis, suggesting that transformation occurs through synergistic dysregulation of cell cycle control induced by misexpression of CK2 and loss of function of p53.
Landesman-Bollag
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Department of Medicine, Boston University Medical Center, Massachusetts 02118, USA.
Channavajhala
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Cardiff
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Seldin
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DC
D000818:Animals; D047390:Casein Kinase II; D018628:Gene Dosage; D016130:Immunophenotyping; D016399:Lymphoma, T-Cell / Q000201:enzymology / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D016296:Mutagenesis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D013950:Thymus Gland / Q000473:pathology; D013953:Thymus Neoplasms / Q000201:enzymology / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*
D016159:Tumor Suppressor Protein p53; D047390:Casein Kinase II; D017346:Protein Serine-Threonine Kinases