Visit our Expo - Redox and Inflammation signaling 2012

Attenuation of MSK1-driven NF-kB gene expression by soy isoflavones does not require
estrogenic activity
Wim Vanden Berghe, Nathalie Dijsselbloem, Linda Vermeulen, 'Matladi N. Ndlovu,
Elke Boone, Guy Haegeman
Laboratory for Eukaryotic Gene Expression and Signal Transduction (LEGEST),
Department of Molecular Biology, Ghent University, K.L. Ledeganckstraat 35, B-9000
Gent, Belgium. Email: w.vandenberghe@ugent.be
We have analysed in molecular detail how soy isoflavones (genistein, daidzein, biochanin A)
suppress NF-kB-driven interleukin-(IL)6 expression. In addition to its physiological immune
function as an acute stress cytokine, sustained elevated expression levels of IL6 promote
chronic inflammatory disorders, aging frailty and tumorigenesis. Our results in estrogenunresponsive
fibroblasts, mitogen- and stress-activated protein kinase (MSK) knock-out cells
and estrogen receptor (ER)-deficient breast tumor cells, demonstrate that phytoestrogenic
isoflavones can selectively block nuclear NF-kB transactivation of specific target genes (in
particular IL6), independently of their estrogenic activity. This occurs via attenuation of
mitogen-activated protein/ERK kinase (MEK) and extracellular signal-regulated kinase
(ERK) activity, which further downregulates MSK-dependent NF-kB p65 and histone H3
phosphorylation. As constitutive NF-kB and MSK activity are hallmarks of aggressive
metastatic ER-deficient breast cancer, the MSK signaling pathway may become an attractive
target for chemotherapy.
Recent references
Vermeulen, L., De Wilde, G., Van Damme, P., Vanden Berghe, W. & Haegeman, G.
Transcriptional activation of the NF-!B p65 subunit by mitogen- and stress-activated protein
kinase-1 (MSK1). EMBO Journal, 22(6), 1313-1324, 2003.
De Bosscher, K., Vanden Berghe, W. & Haegeman, G. The interplay between nuclear receptors
and NF-!B or AP1: molecular mechanisms for gene repression.
Endocr. Rev., 24(4), 488-522, 2003.
Dijsselbloem, N., Vanden Berghe, W., De Naeyer, A. en Haegeman, G. Phyto-estrogens:
multi-purpose compounds at the crossroad of hormone replacement, anti-cancer and antiinflammatory
therapy? Biochem. Pharm., 68, 1171-1185, 2004.
De Bosscher, K., Vanden Berghe, W., Beck, I., Lauw, A., Hapgood, J. & Haegeman, G. Antiinflammatory
capacities of a plant-derived, non-steroidal contraceptive compound. Proc Natl
Acad Sci U S A. [Epub ahead of print 21 october] , 2005
De Naeyer, A., Vanden Berghe, W., Pocock, V., Milligan, S., Haegeman, G., De
Keukeleire, D. : Estrogenic and anticarcinogenic properties of kurarinone, a
lavandulyl flavanone from the roots of Sophora flavescens. Journal of Natural Products, 67
(11): 1829-1832, 2004.
De Naeyer, A., Vanden Berghe, W., De Keukeleire, D. & Haegeman, G. Phytoestrogens in
cancer chemoprevention; characterization and beneficial effects of a new flavanone,
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