Estrogen receptor-alpha binds p53 tumor suppressor protein directly and represses its function.
Estrogen receptor-alpha (ERalpha) promotes proliferation of breast cancer cells, whereas tumor suppressor protein p53 impedes proliferation of cells with genomic damage. Whether there is a direct link between these two antagonistic pathways has remained unclear. Here we report that ERalpha binds directly to p53 and represses its function. The activation function-2 (AF-2) domain of ERalpha and the C-terminal regulatory domain of p53 are necessary for the interaction. Knocking down p53 and ERalpha by small interfering RNA elicits opposite effects on p53-target gene expression and cell cycle progression. Remarkably, ionizing radiation that causes genomic damage disrupts the interaction between ERalpha and p53. Ionizing radiation together with ERalpha knock down results in additive effect on transcription of endogenous p53-target gene p21 (CDKN1) in human breast cancer cells. Our findings reveal a novel mechanism for regulating p53 and suggest that suppressing p53 function is an important component in the pro-proliferative role of ERalpha.
Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm & Carlton Sts., Buffalo, NY 14263, USA.
Wensheng
W
Liu
Santhi D
SD
Konduri
Sanjay
S
Bansal
Bijaya K
BK
Nayak
Sigrid A
SA
Rajasekaran
Sankunny M
SM
Karuppayil
Ayyappan K
AK
Rajasekaran
Gokul M
GM
Das
D001943:Breast Neoplasms / Q000378:metabolism; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000378:metabolism / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000378:metabolism; D011839:Radiation, Ionizing; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D015533:Transcriptional Activation; D014162:Transfection; D019076:Transgenes; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D050759:Cyclin-Dependent Kinase Inhibitor p21; D047628:Estrogen Receptor alpha; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53