Knockout mice reveal a tumor suppressor function for Testin.
The Testin (TES) gene was previously identified as a putative human tumor suppressor gene at 7q31.2, a region that is frequently deleted in hematopoietic malignancies, as well as in epithelial tumors. To determine whether TES acts as a tumor suppressor in vivo, we generated a Tes knockout mouse and then used it in an established model of carcinogen-induced gastric cancer. In mice a zinc-deficient (ZD) diet enhances cellular proliferation in the forestomach and susceptibility to N-nitrosomethylbenzylamine (NMBA)-induced carcinogenesis. Five-week-old Tes wild-type (+/+), heterozygous (+/-), and homozygous (-/-) mice were divided into four groups: mice fed a zinc-sufficient diet (ZS); mice fed a ZD diet; ZS fed plus NMBA-treated mice (ZS+NMBA), and ZD fed plus NMBA-treated mice (ZD+NMBA). After 4 weeks, the ZS+NMBA and ZD+NMBA groups were treated with three intragastric doses of NMBA. Animals were killed 8 weeks after NMBA administration: 25% of +/+ mice developed benign lesions; 88% of +/- showed multiple papillomas, atypical glandular metaplasia, and squamous cell carcinomasl; and 81% of -/- mice displayed very large papillomas, squamous cell carcinomas, and adenocarcinomas. A statistically significant difference in tumor incidence was found between +/- versus +/+ and -/- versus +/+ (P < 0.0001). These data suggest that Tes functions as a tumor suppressor gene in vivo.
Drusco
Alessandra
A
Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA.
Zanesi
Nicola
N
Roldo
Claudia
C
Trapasso
Francesco
F
Farber
John L
JL
Fong
Louise Y
LY
Croce
Carlo M
CM
D000230:Adenocarcinoma / Q000209:etiology / Q000235:genetics / Q000473:pathology; D000818:Animals; D001483:Base Sequence; D002273:Carcinogens / Q000633:toxicity; D002294:Carcinoma, Squamous Cell / Q000209:etiology / Q000235:genetics / Q000473:pathology; D003598:Cytoskeletal Proteins; D004247:DNA / Q000235:genetics; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D004128:Dimethylnitrosamine / Q000031:analogs & derivatives / Q000633:toxicity; D005260:Female; D016147:Genes, Tumor Suppressor; D008297:Male; D008679:Metaplasia; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010212:Papilloma / Q000209:etiology / Q000235:genetics / Q000473:pathology; D016601:RNA-Binding Proteins; D013274:Stomach Neoplasms / Q000209:etiology / Q000235:genetics / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015032:Zinc / Q000008:administration & dosage / Q000172:deficiency
D002273:Carcinogens; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D016601:RNA-Binding Proteins; C093661:Tes protein, mouse; D025521:Tumor Suppressor Proteins; D004247:DNA; C014707:nitrosobenzylmethylamine; D015032:Zinc; D004128:Dimethylnitrosamine