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Retinoblastoma and Wilms' tumour genes — paradigms for tumour suppressor genes
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tion. By comparing the spot frequencies in inversion-free and in inversion-heterozygous flies we can estimate the relative proportions at which recombination or other mechanisms are responsible for the effects observed. Most test compounds reacting with DNA or interfering with DNA synthesis in various ways show a predominance of spots derived from recombination, but exclusive recombinogens or exclusive mutagens seem to be rather rare.
chromosome 11 has now been isolated. This encodes a zinc finger protein, likely to be a transcription factor. We have obtained evidence showing that this gene is likely to play a specific role in normal kidney and gonad development. This contrasts with the Rb gene which is expressed ubiquitously.
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10 Hastie, N., MRC Human Genetics Unit, Edinburgh (U.K.) Retinoblastoma and Wilms' tumour genes - paradigms for turnout suppressor genes
Rare childhood cancers, particularly retinoblastoma, have provided us with excellent models for the role of genetic predisposition in cancer. In the 1970s Knudson proposed a 2-hit mutation model for the development of retinoblastoma and went on to propose that loss of function of the retinoblastoma gene was the essential step in oncogenesis. The location of the retinoblastoma gene was known through the few rare cases associated with deletions at chromosome 13q14. Cavenee et al. developed an elegant genetic approach to confirm the 2-hit hypothesis and to prove that this locus is involved in the majority of retinoblastomas. The assay was based on showing the loss of constitutional heterozygosity (allele loss) for DNA markers on chromosome 13 in turnouts. This approach has now been extended to common cancers where it has proved successful in pinpointing other tumour suppressor gene loci. The retinoblastoma gene has now been isolated and shown to encode a DNA-binding protein which is likely to play a role in the cell cycle. In retinoblastoma it is clear that mutations at only the single locus on chromosome 13 are necessary. This contrasts with the situation for Wilms' tumour (WT), a paediatric malignancy of the kidney in which several different genetic loci may play a role. A candidate WT suppressor gene mapping at one of these loci on
Farmer, P.B., E. Bailey, A. Brooks and Y.-S. Tang, MRC Toxicology Unit, MRC Laboratories, Woodmansterne Road, Carshalton, Surrey SM5 4EF (U.K.) Biomonitoring of human exposure to carcinogens by measurement of haemoglobin adducts
Biological monitoring techniques have been developed to quantify the exposure of man to environmental genotoxic agents by measurements of the covalent adducts that these agents form with amino acids in haemoglobin. For example a modified Edman degradation procedure may be used to determine adducts formed by low-molecularweight alkylating agents with the N-terminal amino acid (valine) in haemoglobin. This procedure produces a thiohydantoin derivative which may be extracted from the protein residue and analysed with high sensitivity by gas chromatography-mass spectrometry (GC-MS). The most extensively studied valine adduct is the hydroxy-ethylated derivative whose content in haemoglobin is increased for example in cigarette smokers and in ethylene oxide-exposed workers. We have also recently illustrated (in collaboration with Dr G. McVie) that N-hydroxyethylvaline levels in haemoglobin increase following treatment of patients with anti-cancer chloroethylnitrosoureas (ACNU, TCNU, fotemustine), suggesting that monitoring of patients on anti-cancer therapy for circulating genotoxic intermediates may be feasible. Exposure to aromatic amines results in the formation of sulphinamide adducts with cysteine residues in haemoglobin which may be determined by GC-MS following hydrolysis to the free amines.
tion. By comparing the spot frequencies in inversion-free and in inversion-heterozygous flies we can estimate the relative proportions at which recombination or other mechanisms are responsible for the effects observed. Most test compounds reacting with DNA or interfering with DNA synthesis in various ways show a predominance of spots derived from recombination, but exclusive recombinogens or exclusive mutagens seem to be rather rare.
chromosome 11 has now been isolated. This encodes a zinc finger protein, likely to be a transcription factor. We have obtained evidence showing that this gene is likely to play a specific role in normal kidney and gonad development. This contrasts with the Rb gene which is expressed ubiquitously.
11
10 Hastie, N., MRC Human Genetics Unit, Edinburgh (U.K.) Retinoblastoma and Wilms' tumour genes - paradigms for turnout suppressor genes
Rare childhood cancers, particularly retinoblastoma, have provided us with excellent models for the role of genetic predisposition in cancer. In the 1970s Knudson proposed a 2-hit mutation model for the development of retinoblastoma and went on to propose that loss of function of the retinoblastoma gene was the essential step in oncogenesis. The location of the retinoblastoma gene was known through the few rare cases associated with deletions at chromosome 13q14. Cavenee et al. developed an elegant genetic approach to confirm the 2-hit hypothesis and to prove that this locus is involved in the majority of retinoblastomas. The assay was based on showing the loss of constitutional heterozygosity (allele loss) for DNA markers on chromosome 13 in turnouts. This approach has now been extended to common cancers where it has proved successful in pinpointing other tumour suppressor gene loci. The retinoblastoma gene has now been isolated and shown to encode a DNA-binding protein which is likely to play a role in the cell cycle. In retinoblastoma it is clear that mutations at only the single locus on chromosome 13 are necessary. This contrasts with the situation for Wilms' tumour (WT), a paediatric malignancy of the kidney in which several different genetic loci may play a role. A candidate WT suppressor gene mapping at one of these loci on
Farmer, P.B., E. Bailey, A. Brooks and Y.-S. Tang, MRC Toxicology Unit, MRC Laboratories, Woodmansterne Road, Carshalton, Surrey SM5 4EF (U.K.) Biomonitoring of human exposure to carcinogens by measurement of haemoglobin adducts
Biological monitoring techniques have been developed to quantify the exposure of man to environmental genotoxic agents by measurements of the covalent adducts that these agents form with amino acids in haemoglobin. For example a modified Edman degradation procedure may be used to determine adducts formed by low-molecularweight alkylating agents with the N-terminal amino acid (valine) in haemoglobin. This procedure produces a thiohydantoin derivative which may be extracted from the protein residue and analysed with high sensitivity by gas chromatography-mass spectrometry (GC-MS). The most extensively studied valine adduct is the hydroxy-ethylated derivative whose content in haemoglobin is increased for example in cigarette smokers and in ethylene oxide-exposed workers. We have also recently illustrated (in collaboration with Dr G. McVie) that N-hydroxyethylvaline levels in haemoglobin increase following treatment of patients with anti-cancer chloroethylnitrosoureas (ACNU, TCNU, fotemustine), suggesting that monitoring of patients on anti-cancer therapy for circulating genotoxic intermediates may be feasible. Exposure to aromatic amines results in the formation of sulphinamide adducts with cysteine residues in haemoglobin which may be determined by GC-MS following hydrolysis to the free amines.