© 1998 by Oxford University Press
Journal Of The National Cancer Institute, Vol 90, 381-388, Copyright © 1998 by Oxford University Press
Y Zhou and AS Lee
BACKGROUND: Soy products contain high levels of genistein, a phytoestrogen
that is a potent inhibitor of cell proliferation and angiogenesis.
Genistein has been found to inhibit the growth of carcinogen-induced
cancers in rats and human leukemia cells transplanted into mice. The
induction of stress proteins (e.g., glucose- related proteins and heat
shock proteins) in tumor cells has been shown to protect them against
programmed cell death; this stress response is inhibited by genistein. The
mechanism(s) by which genistein affects certain stress response genes was
explored in this study. METHODS: Mammalian cell cultures were treated with
azetidine, a proline analog, which elicits a stress response that includes
the induction of the expression of glucose-regulated protein GRP78 and heat
shock protein HSP70. The effects of azetidine and/or genistein treatment on
cellular levels of grp78 and hsp70 messenger RNAs and proteins were
measured by northern blot hybridization and western blot analyses,
respectively, and the binding of nuclear factors to sequence motifs in the
upstream (promoter) regions of these two genes were examined by
electrophoretic mobility shift assays. RESULTS: Genistein antagonized the
binding of a specific transcription factor, nuclear factor-Y/CCAAT binding
factor (NF-Y/CBF), to the CCAAT sequence element most proximal to the
transcription start sites in the hsp70 and grp78 promoters; this CCAAT
element was previously shown to be necessary for full-stress inducibility
of both genes. Treatment of cells with genistein converted NF-Y/CBF into a
nonbinding, transcriptionally inactive form. IMPLICATION: The anticancer
effects of genistein may be related to its ability to reduce the expression
of stress response-related genes.
ARTICLES
Mechanism for the suppression of the mammalian stress response by genistein, an anticancer phytoestrogen from soy
Department of Biochemistry and Molecular Biology, USC/Norris Comprehensive Cancer Center, University of Southern California School of Medicine, Los Angeles 90033, USA.
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