Amplification and overexpression of oncogene Mdm2 and orphan receptor gene Nr1h4 in immortal PRKDC knockout cells.
DNA-dependent protein kinase (DNA-PK) is required for the repair of double strand DNA breaks by nonhomologous DNA end joining. The catalytic subunit of DNA-PK, PRKDC, may also be involved in repair-related or separate cell signaling pathways. To learn more about the cellular function of DNA-PK under normal physiological conditions, we identified genes that are differentially expressed between an immortalized wild-type mouse fibroblast cell line and its DNA-PK-deficient counterpart (Prkdc -/-). The proto-oncogene Mdm2 and the farnesoid X receptor gene Nrlh4 were overexpressed in the DNA-PK-deficient cell line. We show that in the DNA-PK-deficient cell line the genes for both Mdm2 and Nrlh4 are amplified to a degree that could account for most, if not all, of their increased expression. Other genes were strongly downregulated in the DNA-PK-deficient cell line, but this opposite expression pattern was not due to gene amplification in the wild-type cells. None of these genes was differentially expressed in DNA-PK-containing and DNA-PK-deficient primary mouse embryo fibroblasts. Our results suggest a model in which DNA-PK indirectly affects the cellular gene expression profile through its caretaker role and by preventing gene amplification.
Ai
Rong
R
Torrey Pines Institute for Molecular Studies, 3550 General Atomics Court, San Diego, CA 92121, USA.
Sandoval
Ana
A
Chen
David J
DJ
Burma
Sandeep
S
Labhart
Paul
P
D000818:Animals; D002460:Cell Line; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005347:Fibroblasts / Q000737:chemistry / Q000378:metabolism; D005784:Gene Amplification / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism; D011995:Recombination, Genetic / Q000502:physiology; D017384:Sequence Deletion; D014157:Transcription Factors; D015854:Up-Regulation / Q000235:genetics / Q000502:physiology*; D000099150:Receptor, Farnesoid X-Activated
D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051736:Proto-Oncogene Proteins c-mdm2; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C497207:Mdm2 protein, mouse; C497264:Prkdc protein, mouse