Gene expression profiling reveals that the regulation of estrogen-responsive element-independent genes by 17 beta-estradiol-estrogen receptor beta is uncoupled from the induction of phenotypic changes in cell models.
Estrogen hormone 17beta-estradiol (E(2)) is involved in the physiology and pathology of many tissues. E(2) information is conveyed by the transcription factors estrogen receptors (ER) alpha and beta that mediate a complex array of nuclear and non-nuclear events. The interaction of ER with specific DNA sequences, estrogen-responsive elements (EREs), constitutes a critical nuclear signaling pathway. In addition, E(2)-ER regulates transcription through interactions with transfactors bound to their cognate regulatory elements on DNA, hence the ERE-independent signaling pathway. However, the relative importance of the ERE-independent pathway in E(2)-ERbeta signaling is unclear. To address this issue, we engineered an ERE-binding defective ERbeta mutant (ERbeta(EBD)) by changing critical residues in the DNA-binding domain required for ERE binding. Biochemical and functional studies revealed that ERbeta(EBD) signaled exclusively through the ERE-independent pathway. Using the adenovirus infected ER-negative cancer cell models, we found that although E(2)-ERbeta(EBD) regulated the expression of a number of genes identified by microarrays, it was ineffective in altering cellular proliferation, motility, and death in contrast to E(2)-ERbeta. Our results indicate that genomic responses from the ERE-independent pathway to E(2)-ERbeta are not sufficient to alter the cellular phenotype. These findings suggest that the ERE-dependent pathway is a required signaling route for E(2)-ERbeta to induce cellular responses.
Li
Xiaodong
X
Departments of Biochemistry and Biophysics, University of Rochester Medical School, Rochester, New York 14642, USA.
Nott
Stephanie L
SL
Huang
Yanfang
Y
Hilf
Russell
R
Bambara
Robert A
RA
Qiu
Xing
X
Yakovlev
Andrei
A
Welle
Stephen
S
Muyan
Mesut
M
D045744:Cell Line, Tumor; D004273:DNA, Neoplasm / Q000378:metabolism; D004958:Estradiol / Q000502:physiology*; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D008954:Models, Biological; D010641:Phenotype; D011485:Protein Binding / Q000235:genetics; D020218:Response Elements / Q000235:genetics / Q000502:physiology*
D004273:DNA, Neoplasm; D047629:Estrogen Receptor beta; D004958:Estradiol