Tissue-specific sensitivity to AID expression in transgenic mouse models.
Activation-induced cytidine deaminase (AID), an enzyme with homology to members of the APOBEC family, is involved in somatic hypermutation (SHM) of immunoglobulin (Ig) genes, either by direct deamination of DNA or by an indirect action through its putative RNA editing activity. AID is able to mutate both Ig-like reporter constructs and selected non-Ig genes in normal B cells and in other cells when ectopically overexpressed in mammalian cells and transgenic mice. However, in spite of the fact that in these transgenic animals AID activity was driven by an ubiquitous promoter, only T lymphomas and lung adenomas occurred. In the present work, we constructed three sets of transgenic mice in which AID was under the control of lck, HTLV-I and MMTV promoters, respectively. The lck/AID mice developed thymic lymphomas with variable but high efficiency, while no tumor was detected in HTLV-I/AID mice after two years of monitoring. Four MMTV/AID founder mice died with an atypical clinical picture, although no mammary tumor was found. These findings suggest that additional factors, present in thymocytes but not in other tissues or in lymphoid cells at different stages of differentiation, are needed for AID to fully manifest its tumorigenic potential in mouse. Alternatively, the display of full AID mutagenic and transforming activity could be related to the existence of physiologic DSBs which occur in both thymocytes and switching B cells.
Rucci
Francesca
F
Human Genome Department, Istituto di Tecnologie Biomediche, CNR, Segrate (MI), Italy.
Cattaneo
Leonardo
L
Marrella
Veronica
V
Sacco
Maria Grazia
MG
Sobacchi
Cristina
C
Lucchini
Franco
F
Nicola
Stefania
S
Della Bella
Silvia
S
Villa
Maria Luisa
ML
Imberti
Luisa
L
Gentili
Francesca
F
Montagna
Cristina
C
Tiveron
Cecilia
C
Tatangelo
Laura
L
Facchetti
Fabio
F
Vezzoni
Paolo
P
Villa
Anna
A
D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation; D002471:Cell Transformation, Neoplastic; D003564:Cytidine Deaminase / Q000235:genetics* / Q000378:metabolism*; D018076:DNA, Complementary / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D015870:Gene Expression; D019674:Genes, T-Cell Receptor beta; D016259:Genes, myc; D016158:Genes, p53; D015368:Human T-lymphotropic virus 1 / Q000235:genetics; D007668:Kidney / Q000201:enzymology / Q000473:pathology; D008099:Liver / Q000201:enzymology / Q000473:pathology; D008198:Lymph Nodes / Q000201:enzymology / Q000473:pathology; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000235:genetics; D008321:Mammary Glands, Animal / Q000201:enzymology / Q000473:pathology; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D011401:Promoter Regions, Genetic; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D014018:Tissue Distribution; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D018076:DNA, Complementary; D004268:DNA-Binding Proteins; C499308:Rag2 protein, mouse; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase