Transcriptional responses to estrogen and progesterone in mammary gland identify networks regulating p53 activity.
Estrogen and progestins are essential for mammary growth and differentiation but also enhance the activity of the p53 tumor suppressor protein in the mammary epithelium. However, the pathways by which these hormones regulate p53 activity are unknown. Microarrays were used to profile the transcriptional changes within the mammary gland after administration of either vehicle, 17beta-estradiol (E), or progesterone (P) individually and combined (EP). Treatment with EP yielded 1182 unique genes that were differentially expressed compared to the vehicle-treated group. Although 30% of genes were responsive to either E or P individually, combined treatment with both EP had a synergistic effect accounting for 60% of the differentially regulated genes. Analysis of protein-protein interactions identified p53, RelA, Snw1, and Igfals as common targets of genes regulated by EP. RelA and p53 form hubs within a network connected by genes that are regulated by EP and that may coordinate the competing functions of RelA and p53 in proliferation and survival of cells. Induction of early growth response 1 (Egr1) and Stratifin (Sfn) (also known as 14-3-3sigma) by EP was confirmed by reverse transcription-quantitative PCR and shown to be p53 independent. In luciferase reporter assays, Egr1 was shown to enhance transcriptional activation by p53 and inhibit nuclear factor kappaB activity. These results identify a gene expression network that provides redundant activation of RelA to support proliferation as well as sensitize p53 to ensure proper surveillance and integration of their competing functions through factors such as Egr1, which both enhance p53 and inhibit RelA.
Department of Veterinary and Animal Sciences, 161 Holdsworth Way, Paige Laboratory, University of Massachusetts, Amherst, Massachusetts 01003, USA.
Shaolei
S
Lu
Klaus A
KA
Becker
Mary J
MJ
Hagen
Haoheng
H
Yan
Amy L
AL
Roberts
Lesley A
LA
Mathews
Sallie S
SS
Schneider
Hava T
HT
Siegelmann
Kyle J
KJ
MacBeth
Stephen M
SM
Tirrell
Jeffrey L
JL
Blanchard
D Joseph
DJ
Jerry
D048948:14-3-3 Proteins / Q000235:genetics; D000818:Animals; D001943:Breast Neoplasms; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D051766:Early Growth Response Protein 1 / Q000235:genetics; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D004848:Epithelium / Q000187:drug effects / Q000502:physiology; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008321:Mammary Glands, Animal / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D016328:NF-kappa B / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010052:Ovariectomy; D011374:Progesterone / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects* / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism*
D048948:14-3-3 Proteins; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D016328:NF-kappa B; C499130:Sfn protein, mouse; D016159:Tumor Suppressor Protein p53; D011374:Progesterone; D004958:Estradiol