Molecular bases for hereditary cancer-prone diseases.
Constitutional loss or inactivation of one copy of a tumor-suppressor gene, as exemplified by hereditary retinoblastoma, increases the propensity for malignancies by reducing the number of events necessary for the complete loss of the negative regulatory function. We developed a selectable mutation assay employing a human lymphoblastoid cell line (LCL) derived from a heterozygous carrier of 2,8-dihydroxyadenine urolithiasis, adenine phosphoribosyltransferase (APRT) deficiency, for dissecting the second step in loss-of-function mutations and for determining the potential of physical and chemical agents for producing such mutations. The mode of mutational events arising in the wild-type allele of the functionally heterozygous APRT gene resembled that reported for tumor-suppressor genes in malignancies in that mitotic non-disjunctions or recombinations as well as deletions prevailed. Ultraviolet light (UV) was much less efficient in inducing these types of mutations than ionizing radiation. A group of autosomal recessive cancer-prone diseases, including xeroderma pigmentosum (XP), has been characterized as being more susceptible to genomic insults, owing to some defects in DNA processing, such as replication, repair, or recombination. This increased genomic instability may accelerate the gain-of-function mutation at a proto-oncogene and/or the loss-of-function mutation at a tumor-suppressor gene. XP complementation group A (XP-A) LCLs were extremely sensitive to UV-mutagenesis at the hypoxanthine phosphoribosyltransferase (HPRT) locus even at equicytotoxic doses. Some unique mechanism may operate in UV-mutagenesis in XP-A. We have succeeded for the first time in rendering XP-A cells tumorigenic in athymic mice by applying multiple exposures to UV and subsequent treatment with TPA.(ABSTRACT TRUNCATED AT 250 WORDS)
Tatsumi
K
K
Department of Molecular Oncology, Faculty of Medicine, Kyoto University, Japan.
Tachibana
A
A
Fujimori
A
A
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004198:Disease Susceptibility; D016147:Genes, Tumor Suppressor / Q000235:genetics; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009369:Neoplasms / Q000150:complications / Q000235:genetics*; D000090063:Proto-Oncogene Mas; D012871:Skin Diseases / Q000150:complications / Q000235:genetics*; D012878:Skin Neoplasms / Q000235:genetics; D014407:Tumor Cells, Cultured; D014983:Xeroderma Pigmentosum / Q000235:genetics