Epithelial cell cycling predicts p53 responsiveness to gamma-irradiation during post-natal mammary gland development.
The tumor suppressor gene, TP53, plays a major role in surveillance and repair of radiation-induced DNA damage. In multiple cell types, including mammary epithelial cells, abrogation of p53 (encoded by Trp53) function is associated with increased tumorigenesis. We examined gamma-irradiated BALB/c-Trp53(+/+) and -Trp53(-/-) female mice at five stages of post-natal mammary gland development to determine whether radiation-induced p53 activity is developmentally regulated. Our results show that p53-mediated responses are attenuated in glands from irradiated virgin and lactating mice, as measured by induction of p21/WAF1 (encoded by Cdkn1a) and apoptosis, while irradiated early- and mid-pregnancy glands exhibit robust p53 activity. There is a strong correlation between p53-mediated apoptosis and the degree of cellular proliferation, independent of the level of differentiation. In vivo, proliferation is intimately influenced by steroid hormones. To determine whether steroid hormones directly modulate p53 activity, whole organ cultures of mammary glands were induced to proliferate using estrogen plus progesterone or epidermal growth factor plus transforming growth factor-alpha and p53 responses to gamma-irradiation were measured. Regardless of mitogens used, proliferating mammary epithelial cells show comparable p53 responses to gamma-irradiation, including expression of nuclear p53 and p21/WAF1 and increased levels of apoptosis, compared to non-proliferating irradiated control cultures. Our study suggests that differences in radiation-induced p53 activity during post-natal mammary gland development are influenced by the proliferative state of the gland, and may be mediated indirectly by the mitogenic actions of steroid hormones in vivo.
Minter
Lisa M
LM
Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, MA 01003, USA.
Dickinson
Ellen S
ES
Naber
Stephen P
SP
Jerry
D Joseph
DJ
D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation / Q000187:drug effects / Q000528:radiation effects; D002455:Cell Division / Q000235:genetics / Q000528:radiation effects; D002467:Cell Nucleus / Q000378:metabolism / Q000528:radiation effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism / Q000528:radiation effects*; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D005720:Gamma Rays; D005786:Gene Expression Regulation; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000254:growth & development* / Q000528:radiation effects; D051379:Mice; D008817:Mice, Mutant Strains; D009924:Organ Culture Techniques; D011247:Pregnancy; D011374:Progesterone / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism / Q000528:radiation effects*
C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004967:Estrogens; D016159:Tumor Suppressor Protein p53; D011374:Progesterone