Variation in the expression of p53, c-myc, and bcl-2 oncoproteins in individual patient cultures of normal urothelium exposed to cobalt 60 gamma-rays and N-nitrosodiethanolamine.
The controls determining the initial response of cells to DNA damage probably determine whether a cancer will ultimately occur. Efficient repair or apoptosis represents extremes of control mechanisms. Misrepair can lead to fixation of damage. The changes in oncoprotein expression of three genes involved in the regulation of repair of DNA damage and postdamage proliferation of cells were measured in cultures of normal urothelium from 55 patients without any malignancy. The aim was to obtain information on interperson variation in response to carcinogens in the human population. The group included 10 pediatric patients < 2 years old. Two different carcinogenic agents, ionizing radiation and N-nitrosodiethanolamine, which represent widely different DNA-damaging pathways, were used. Both of these cause bladder cancer in humans. Cells from explanted tissue were examined after carcinogen exposure for levels of p53, c-myc, and bcl-2 proteins. Both carcinogens led to increased levels of cytoplasmic p53 protein expression, although there was significant interpatient variation. bcl-2 showed a very significant increase in expression after radiation exposure. c-myc was high and variable pre- and postexposure. Individual patient culture changes in the expression of the three oncoproteins did not correlate significantly with each other or with cell growth, suggesting that the controls are complex. Pediatric samples had lower mean control values of p53 and bcl-2 than did adult samples. This was due to the absence in this group of high controls seen in some adult cultures. The result suggest that an early breakdown in control mechanisms of growth arrest and apoptosis may occur in urothelium after carcinogen exposure.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Urology, Royal Liverpool University Hospital, United Kingdom.
J V
JV
Harney
C B
CB
Seymour
D M
DM
Murphy
C
C
Mothersill
D000328:Adult; D002273:Carcinogens / Q000008:administration & dosage / Q000494:pharmacology*; D002478:Cells, Cultured; D003037:Cobalt Radioisotopes; D004249:DNA Damage; D004052:Diethylnitrosamine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D004848:Epithelium; D015870:Gene Expression / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D007223:Infant; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000187:drug effects / Q000528:radiation effects; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000187:drug effects / Q000528:radiation effects; D011839:Radiation, Ionizing; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000187:drug effects / Q000528:radiation effects; D001743:Urinary Bladder / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects
D002273:Carcinogens; D003037:Cobalt Radioisotopes; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D016159:Tumor Suppressor Protein p53; C014129:N-nitrosodiethanolamine; D004052:Diethylnitrosamine