Autoimmunity, spontaneous tumourigenesis, and IL-15 insufficiency in mice with a targeted disruption of the tumour suppressor gene Fus1.
The Fus1 gene resides in the critical 3p21.3 human chromosomal region deleted in lung and breast cancers. Recently, the tumour suppressor properties of Fus1 were confirmed experimentally by intra-tumoural administration of Fus1 that suppressed experimental lung metastasis in mice. We generated Fus1-deficient mice that were viable, fertile, and demonstrated a complex immunological phenotype. Animals with a disrupted Fus1 gene developed signs of autoimmune disease, such as vasculitis, glomerulonephritis, anaemia, circulating autoantibodies, and showed an increased frequency of spontaneous vascular tumours. Preliminary analysis of immune cell populations revealed a consistent defect in NK cell maturation in Fus1 null mice that correlated with changes in the expression of IL-15. Injection of IL-15 into Fus1 knockout mice completely rescued the NK cell maturation defect. Based on these results, we propose the hypothesis that Fus1 deficiency affects NK cell maturation through the reduction of IL-15 production but does not directly alter their developmental capacity. Since acquired immunity was not affected in Fus1-deficient animals, we suggest a relationship between the Fus1 protein and the regulation of innate immunity via IL-15 production. The increased frequency of spontaneous cancers and the development of an autoimmune syndrome in Fus1 null mice imply that these mice could serve as a model for studying molecular mechanisms of anti-tumour immunity and autoimmunity.
Ivanova
A V
AV
Laboratory of Immunobiology, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702, USA.
Ivanov
S V
SV
Laboratory of Immunobiology, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702, USA.
Pascal
V
V
Laboratory of Experimental Immunology, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702, USA.
Lumsden
J M
JM
Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Ward
J M
JM
Comparative Medicine Branch, NIAID, & SoBran, Inc., Rockville, MD 20892 USA.
Morris
N
N
Laboratory Animal Sciences Program, National Cancer Institute at Frederick, Frederick, MD 21702, USA.
Tessarolo
L
L
Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702, USA.
Anderson
S K
SK
Laboratory of Experimental Immunology, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702, USA.
Lerman
M I
MI
Basic Research Laboratory, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702, USA.
D000818:Animals; D015551:Autoimmunity / Q000235:genetics* / Q000276:immunology; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D006391:Hemangioma / Q000235:genetics / Q000276:immunology; D006394:Hemangiosarcoma / Q000235:genetics / Q000276:immunology; D007113:Immunity, Innate / Q000276:immunology; D019409:Interleukin-15 / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology; D051379:Mice; D008928:Mitochondria / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology; D009369:Neoplasms / Q000235:genetics* / Q000276:immunology; D010641:Phenotype; D011498:Protein Precursors / Q000032:analysis / Q000172:deficiency / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D014018:Tissue Distribution / Q000235:genetics; D025521:Tumor Suppressor Proteins; D014452:Ubiquitins / Q000032:analysis / Q000172:deficiency / Q000235:genetics*; D014657:Vasculitis / Q000235:genetics
D019409:Interleukin-15; D009363:Neoplasm Proteins; D011498:Protein Precursors; D012333:RNA, Messenger; C499993:TUSC2 protein, human; D025521:Tumor Suppressor Proteins; C543627:Tusc2 protein, mouse; D014452:Ubiquitins; C045677:ubiquitin precursor