Targeting estrogen responsive elements (EREs): design of potent transactivators for ERE-containing genes.
The estrogen hormone (E2) plays an important role in the physiology and pathophysiology of target tissues. The effects of E2 are conveyed by the estrogen receptors (ER) alpha and beta. The E2-ER complex mediates an array of genomic and non-genomic events that orchestrate the expression of a number of genes involved in the regulation of cell proliferation and differentiation. The interaction of with the regulatory DNA sequence, estrogen responsive element (ERE), of each responsive gene constitutes a critical genomic signaling pathway. However, the relative importance of ERE-dependent E2-ER signaling in cell proliferation remains to be elucidated. To address this issue, we engineered ERE-binding activators (EBAs) that specifically and potently regulate ERE-containing genes. The modular nature of ER allowed us to initially design a monomeric ERE-binding module by genetically joining two DNA-binding domains with the hinge domain. Integration of strong activation domains from other transcription factors into this module generated constitutively active EBAs. These transactivators robustly induced the expression of only ERE-containing promoter constructs in transfected cells independent of ligand, dimerization, ER-subtype and -status. Moreover, EBAs altered cell cycle progression in breast cancer cell lines in a manner similar to E2-ER. These results demonstrate the importance of ERE-containing genes in the regulation of cell proliferation. These novel ERE-binding transregulators could also be a basis for the targeted regulation of ERE-containing genes, the identification of estrogen responsive gene networks, and the development of alternative/complementary therapeutic approaches for estrogen target tissue cancers.
Huang
Jing
J
Department of Biochemistry and Biophysics, University of Rochester School of Medicine and Dentistry, NY 14642, USA.
Li
Xiaodong
X
Yi
Ping
P
Hilf
Russell
R
Bambara
Robert A
RA
Muyan
Mesut
M
D000818:Animals; D002453:Cell Cycle / Q000502:physiology; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism*; D017930:Genes, Reporter; D011401:Promoter Regions, Genetic; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation
D004268:DNA-Binding Proteins; D004967:Estrogens; D011960:Receptors, Estrogen; D015534:Trans-Activators; D014157:Transcription Factors