Catalytic subunit of DNA-dependent protein kinase: impact on lymphocyte development and tumorigenesis.
basic_science · Level V
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- Record sourced from PubMed, PMID 9990036.
- Also identified by PMC identifier 15475.
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Abstract
The DNA-dependent protein kinase (DNA-PK) consists of a heterodimer DNA-binding complex, Ku70 and Ku80, and a large catalytic subunit, DNA-PKcs. To examine the role of DNA-PKcs in lymphocyte development, radiation sensitivity, and tumorigenesis, we disrupted the mouse DNA-PKcs by homologous recombination. DNA-PKcs-null mice exhibit neither growth retardation nor a high frequency of T cell lymphoma development, but show severe immunodeficiency and radiation hypersensitivity. In contrast to the Ku70-/- and Ku80-/- phenotype, DNA-PKcs-null mice are blocked for V(D)J coding but not for signal-end joint formation. Furthermore, inactivation of DNA-PKcs leads to hyperplasia and dysplasia of the intestinal mucosa and production of aberrant crypt foci, suggesting a novel role of DNA-PKcs in tumor suppression.
Medical subject headings
- Antigens, Nuclear
- Cell Transformation, Neoplastic
- DNA Helicases
- DNA-Binding Proteins
- Immunologic Deficiency Syndromes
- Intestinal Mucosa
- Intestinal Neoplasms
- Nuclear Proteins
- Precancerous Conditions
- Protein Serine-Threonine Kinases
- Radiation Tolerance