Formation of an active form of the interleukin-2/15 receptor beta-chain by insertion of the intracisternal A particle in a radiation-induced mouse thymic lymphoma and its role in tumorigenesis.
Although many reports suggest that aberrant regulation of cytokine signaling pathways via the interleukin-2 receptor (IL-2R) induces tumorigenic transformation, constitutively active IL-2R in tumors has not been reported. We searched for genomic alteration of the IL-2/15R beta-subunit gene (IL-2/15R beta) in cytokine-independent cell lines established from radiation-induced mouse thymic lymphomas. In the TL34 cell line and its primary tumor, one of the IL-2/15R beta alleles was rearranged by the insertion of an intracisternal A particle (IAP) retrotransposon. The IAP-IL2/15R beta chimeric gene expressed chimeric mRNA in which IAP-coding Gag-Pol mRNA was fused to IL-2/15R beta mRNA and coded for Gag-Pol-IL-2/15R beta chimeric protein. Forced expression of the Gag-Pol-IL-2/15R beta chimeric cDNA in a mouse cytotoxic T-cell line (CTLL-2) converted IL-2-dependent cell growth to IL-2-independent growth, suggesting that the chimeric protein activates some of the IL-2 signaling pathways necessary for cell proliferation. Downregulation of the expression of the Gag-Pol-IL-2/15R beta chimeric protein in TL34 by antisense RNA inhibited cell growth, and concomitantly reduced the level of c-myc protein. These results suggest that the Gag-Pol-IL-2/15R beta is a constitutively active form that transmits proliferative signals by expressing downstream target genes, including c-myc. Thus, we demonstrated that the chimeric receptor gene produced by the insertion of an IAP functions as an oncogene by providing IL-2-independent autonomous growth potential.
Ukai
Hideki
H
Japan Society for the Promotion of Science, National Institute of Radiological Sciences, Chiba, Japan.
Ishii-Oba
Hiroko
H
Ukai-Tadenuma
Maki
M
Ogiu
Toshiaki
T
Tsuji
Hideo
H
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D003673:Defective Viruses / Q000235:genetics; D015683:Gene Products, gag / Q000235:genetics / Q000378:metabolism; D007426:Genes, Intracisternal A-Particle; D007376:Interleukin-2 / Q000494:pharmacology; D053646:Interleukin-2 Receptor beta Subunit; D008223:Lymphoma / Q000235:genetics* / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D009381:Neoplasms, Radiation-Induced / Q000235:genetics* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D018123:Receptors, Interleukin / Q000235:genetics* / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000473:pathology; D013953:Thymus Neoplasms / Q000235:genetics* / Q000473:pathology; D014407:Tumor Cells, Cultured; D016662:Virus Integration / Q000235:genetics
D015683:Gene Products, gag; C508022:Il2rb protein, mouse; D007376:Interleukin-2; D053646:Interleukin-2 Receptor beta Subunit; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D015375:Receptors, Interleukin-2; D011993:Recombinant Fusion Proteins