The biological function of DNA-PKcs has been clarified as being involved in the genomic organization of the T-cell receptor and immunoglobulin genes and also in the non-homologous end-joining repair pathway for DNA double-strand breaks (DSBs) (for a review, see ref. The genetic defect in the severe combined immunodeficiency (Scid) mouse has been recently characterized as an intragenic mutation at the 3′-end of the gene encoding a catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) ( 1 ). The present study clearly demonstrated high susceptibility of Scid mice to colon carcinogenesis, which might be attributable to disruption of the caretaker role of DNA-PK in colonic epithelial cells.ĪC, aberrant crypt, ACF, aberrant crypt focus, AOM, azoxymethane, DNA-PKcs, catalytic subunit of DNA-dependent protein kinase, DSB, double-strand break, MN, minisatellite, MMR, mismatch repair, O 6 -meG, O 6 -methylguanine, MGMT, O 6 -meG DNA methyltransferase, PCR, polymerase chain reaction, Scid, severe combined immunodeficiency, SSCP, single strand conformation polymorphism. The multiplicity of colon tumors in Scid mice was also significantly higher than in C.B-17 mice, being 2.2 ± 1.5 and 0.9 ± 1.2, respectively ( P < 0.001). The incidences of colon tumors, either adenomas or adenocarcinomas, in Scid and C.B-17 mice after administration of AOM (10 mg/kg body weight/week) for 6 weeks were 87% (26 of 30) and 50% (15 of 30), respectively, by experimental week 22 ( P < 0.01). Significantly higher susceptibility in terms of induction of both aberrant crypt foci (ACFs), putative pre-cancerous lesions of the colon and colon cancers was observed as compared with the isogenic strain, C.B-17 mice. In the present study, the susceptibility of Scid mice to colon carcinogenesis due to administration of azoxymethane (AOM) was investigated. Scid mice are highly susceptible to development of T-cell lymphomas, and because of the nature of its association with DNA repair and recombination, DNA-PKcs is considered to belong to the caretaker class of tumor suppressor genes. Severe combined immunodeficiency (Scid) mice have defects in V(D)J recombination and DNA double-strand breaks repair caused by an inherited genetic defect in the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs).
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