RESUMO
Min (multiple intestinal neoplasia) mice carry a mutant allele of the murine Apc (adenomatous polyposis coli) locus and are predisposed to intestinal adenoma formation in the intestinal tract. Early studies have shown complete loss of function of Apc by whole chromosome loss on the tumor-sensitive C57BL/6J genetic background and in AKR x B6 F1 hybrids. Gamma-radiation-induced chromosomal losses focus the critical region on wt Apc, but because of the limited number of polymorphic markers used, no other critical regions of loss on chromosome 18 were identified. Using intestinal tumors arising spontaneously and induced by X-rays in CBA/H x C57BL/6J F1 hybrid mice and high-resolution microsatellite loss of heterozygosity (LOH) techniques, we provide mapping data for wt Apc loss, which confirms and extends earlier observations. In addition, high-frequency loss events at the Dpc4 locus were found in both spontaneous and radiation-induced tumors. These data identified LOH of Dpc4 as a critical secondary event following complete functional loss of Apc. LOH across the Trp53 genomic region of chromosome 11 was not observed. No LOH was recorded for the Mom1 candidate gene Pla2g2a or for 9 out of 10 polymorphic markers from the Mom1 genomic region on murine chromosome 4. One marker mapping distal to Pla2g2a showed LOH in a small minority of spontaneous tumors. These data support the contention that Mom1 does not act as a classical tumor suppressor. Overall, our data indicates a significant role for Dpc4 mutation in intestinal tumor progression in the mouse and provides further evidence for the importance of interstitial chromosome losses in radiation tumorigenesis.
Assuntos
Proteínas de Ligação a DNA/efeitos da radiação , Genes APC/efeitos da radiação , Neoplasias Intestinais/genética , Perda de Heterozigosidade/efeitos da radiação , Neoplasias Induzidas por Radiação/genética , Transativadores/efeitos da radiação , Animais , Cruzamentos Genéticos , Proteínas de Ligação a DNA/genética , Raios gama , Genes APC/genética , Genes p53/genética , Genes p53/efeitos da radiação , Expectativa de Vida , Perda de Heterozigosidade/genética , Camundongos , Camundongos Endogâmicos AKR , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Mutantes , Repetições de Microssatélites , Transdução de Sinais/genética , Transdução de Sinais/efeitos da radiação , Proteína Smad4 , Transativadores/genética , Raios XRESUMO
The present study, a co-operative project between three European institutes, was aimed at elucidating whether the APC gene in carriers of familial adenomatous polyposis coli (FAP) also causes some genetic sensitivity revealed by DNA damage and the yield of chromosome aberrations in peripheral blood lymphocytes exposed to gamma rays. In addition, it seemed of interest to study whether DNA repair is modified after irradiation of lymphocytes from FAP patients compared to controls. To this end, we have used the inhibition of the poly(ADP-ribose) polymerase (ADPRP) by 3-aminobenzamide (3ABA) and studied the effect of 3ABA on the frequency of DNA strand breaks and chromosome aberrations. The data indicate that FAP is not associated with an increased chromosomal sensitivity towards ionising radiation.
