TY - JOUR
T1 - Tissue-specific sensitivity to AID expression in transgenic mouse models
AU - Rucci, Francesca
AU - Cattaneo, Leonardo
AU - Marrella, Veronica
AU - Sacco, Maria Grazia
AU - Sobacchi, Cristina
AU - Lucchini, Franco
AU - Nicola, Stefania
AU - Della Bella, Silvia
AU - Villa, Maria Luisa
AU - Imberti, Luisa
AU - Gentili, Francesca
AU - Montagna, Cristina
AU - Tiveron, Cecilia
AU - Tatangelo, Laura
AU - Facchetti, Fabio
AU - Vezzoni, Paolo
AU - Villa, Anna
N1 - Funding Information:
This work was supported by grants from FIRB to P.V., L.I. and A.V. (RBNE019J9W) and by Fondazione Beretta, Brescia (to FG). This is manuscript no. 86 of the Genoma 2000/ITB Project funded by CARIPLO.
PY - 2006/8/1
Y1 - 2006/8/1
N2 - 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.
AB - 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.
KW - Activation-induced deaminase
KW - Animal model
KW - Ectopic expression
KW - Thymic lymphomas
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U2 - 10.1016/j.gene.2006.03.024
DO - 10.1016/j.gene.2006.03.024
M3 - Article
C2 - 16787714
AN - SCOPUS:33745934925
SN - 0378-1119
VL - 377
SP - 150
EP - 158
JO - Gene
JF - Gene
IS - 1-2
ER -