Differential effects of novel tumour-derived p53 mutations on the transformation of NIH-3T3 cells.
The p53 tumour suppressor gene is frequently mutated in human tumours and different tumour-derived mutations have varying effects on cells. The effect of a novel tumour-derived p53 mutation and two recently described mutations from South African breast cancer patients on the growth rate, colony formation, cell cycle arrest after irradiation and response to chemotherapeutic drugs was investigated. None of the p53 mutations had any significant effect on the inherent growth rate of the cells; however, contact inhibition of growth in two of the mutants was lost. These same two mutants formed colonies in soft agar, whereas the third mutant did not. All three of the mutants failed to show a G(1) cell cycle arrest after exposure to 7 Gy of [(60)Co] radiation, albeit to different degrees. Cells expressing the p53 mutants were either more sensitive to cisplatin and melphalan or more resistant than the untransfected cells, depending on the mutation. However, there was no difference in response to daunorubicin treatment. These results demonstrate that different p53 mutations exert varying biological effects on normal cells, with some altering checkpoint activation more effectively than others. The data also suggest that the nature of the p53 mutation influences the sensitivity to cytostatic drugs.
Donninger
Howard
H
Division of Medical Biochemistry, Institute for Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Observatory 7925, South Africa.
Binder
Anke
A
Bohm
Lothar
L
Parker
M Iqbal
MI
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D015153:Blotting, Western; D002453:Cell Cycle / Q000502:physiology; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics* / Q000528:radiation effects; D002945:Cisplatin / Q000494:pharmacology; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D003630:Daunorubicin / Q000494:pharmacology; D007150:Immunohistochemistry; D007700:Kinetics; D008558:Melphalan / Q000494:pharmacology; D051379:Mice; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics* / Q000502:physiology*; D041681:NIH 3T3 Cells; D011487:Protein Conformation; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000235:genetics* / Q000502:physiology*
D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D018076:DNA, Complementary; D016159:Tumor Suppressor Protein p53; D002945:Cisplatin; D008558:Melphalan; D003630:Daunorubicin