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Flavonoid Phytochemicals Regulate Activator Protein-1 Signal Transduction Pathways in Endometrial and Kidney Stable Cell Lines
EPA Grant Number: U916008Title: Flavonoid Phytochemicals Regulate Activator Protein-1 Signal Transduction Pathways in Endometrial and Kidney Stable Cell Lines
Investigators: Schief, Lawanda S.
Institution: Tulane University of Louisiana
EPA Project Officer: Edwards, Jason
Project Period: August 1, 2001 through August 1, 2004
Project Amount: $71,660
RFA: STAR Graduate Fellowships (2001)
Research Category: Fellowship - Toxicology , Academic Fellowships , Health Effects
Description:
Objective:The objective of this research project is to examine the effects of certain phytochemicals on the transcription factor activator protein-1 (AP-1).
Approach:Phytochemicals bind to and regulate the human estrogen
receptors (ER
and ER
), mimicking actions of the endogenous estrogen, 17-estradiol,
and known antiestrogens such as ICI 182,780. Recently, however, some of these
estrogenic phytochemicals have been shown to affect other signal transduction
pathways, such as receptor tyrosine kinases and mitogen-activated protein kinases
(MAPK). Previously, we found that certain phytochemicals, such as flavone,
apigenin, kaempferide and chalcone, have potent antiestrogenic activity. However,
the antiestrogenicity of these compounds does not correlate with their ER binding
capacity, suggesting alternative signaling as a mechanism for their antagonistic
effects. Using AP-1-luciferase stable human endometrial adenocarcinoma Ishikawa
and human embryonic kidney (HEK) 293 cells, chalcone, flavone, and apigenin
stimulated AP-1 activity. Additionally, we determined the effects of the phytochemicals
on transcription factors that are downstream targets of various MAPK pathways.
To test this, we used HEK 293 cells stably cointegrated with GAL4 transcriptional
activation systems of Elk-1, c-Jun or C/EBP homologous protein (CHOP). Chalcone
was the only phytochemical that activated all three transcription factors (Elk-1,
2.7-fold [P < 0.001]: c-Jun, 2.7-fold [P = 0.025]; CHOP, 3.0-fold [P = 0.002]),
whereas apigenin stimulated CHOP (3.9-fold; P < 0.001), but inhibited phorbol
myristoyl acetate-induced c-Jun activity (71 percent; P = 0.006). This research
project suggests that phytochemicals affect multiple signaling pathways that
converge at the level of transcriptional regulation. The ability of flavonoids
to regulate MAPK-responsive pathways in a selective manner indicates a mechanism
by which phytochemicals may influence human health and disease.
fellowship, flavonoid phytochemicals, estrogen receptor, ER, mitogen-activated protein kinase, activator protein-1, AP-1.