Human mammary epithelial cells exhibit a differential p53-mediated response following exposure to ionizing radiation or UV light.
The tumor suppressor protein, p53, plays a critical role as a transcriptional activator of downstream target genes involved in the cellular response to DNA damaging agents. We examined the cell cycle checkpoint response of human mammary epithelial cells (HMEC) and their isogenic fibroblast counterparts to ionizing (IR) and ultraviolet (UV) radiation, two genotoxic agents whose DNA damage response pathways involve p53. Using flow cytometric analysis, we found that both mortal and immortalized HMEC, which contain wild-type p53 sequence, do not exhibit a G1 arrest in response to IR, but show an intact G2 checkpoint. Supportive evidence from Western analyses revealed that there was neither an increase in p53 nor one of its downstream targets, p21WAF1, in HMEC exposed to IR. In contrast, isogenic mammary fibroblasts arrest at the G1 checkpoint and induce the p53 and p21WAF1 proteins following IR. By comparison, HMEC exposed to UV displayed an S phase arrest and induced the expression of p53 and p21WAF1. Our results show that the cellular response to DNA damage depends on both the type of damage introduced into the DNA and the specific cell type.
Meyer
K M
KM
Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, NC 27599, USA.
Hess
S M
SM
Tlsty
T D
TD
Leadon
S A
SA
D001940:Breast / Q000166:cytology* / Q000528:radiation effects; D002453:Cell Cycle / Q000528:radiation effects; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis / Q000502:physiology / Q000528:radiation effects; D004847:Epithelial Cells / Q000528:radiation effects*; D005260:Female; D005347:Fibroblasts / Q000528:radiation effects; D016193:G1 Phase / Q000528:radiation effects; D005720:Gamma Rays; D006801:Humans; D011836:Radiation Tolerance; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000502:physiology / Q000528:radiation effects*; D014466:Ultraviolet Rays
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016159:Tumor Suppressor Protein p53