Carcinogenesis, Vol. 21, No. 4, 633-639,
April 2000
© 2000 Oxford University Press
Molecular Epidemiology and Cancer Prevention |
Increase in wild-type p53 stability and transactivational activity by the chemopreventive agent apigenin in keratinocytes
1 Department of Pathology and Laboratory Medicine and
2 Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA and
3 Department of Basic Gerontology National Institute for Longevity Sciences, 36-3 Gengo Morioka-Cho Obu, Aichi 474-8522, Japan
Apigenin, a naturally occurring, non-mutagenic flavonoid, has been shown to inhibit UV-induced skin tumorigenesis in mice when topically applied. In this report we have used the mouse keratinocyte 308 cell line, which contains a wild-type p53 gene, to study the effect of apigenin treatment on p53 protein levels and the expression of its downstream partner, p21/waf1. Cells were treated with 70 µM apigenin for various times and levels of p53 and p21/waf1 protein were assessed by western blot analysis. The level of p53 protein was induced 27-fold after 4 h of apigenin treatment and levels remained elevated through 10 h of exposure. After 24 h of exposure to 70 µM apigenin, p53 protein levels returned to control levels. p21/waf1 protein levels increased ~1.5–2-fold after 4 h and remained elevated at 24 h. To investigate the mechanism of p53 protein accumulation, we compared the half-life of p53 protein in vehicle- and apigenin-treated cells. Cells were incubated for 4 h in the presence of apigenin, then cycloheximide was added to inhibit further protein synthesis and p53 protein levels were measured by western blot. The half-life of p53 protein was found to be increased an average of 8-fold in apigenin-treated cells compared with vehicle-treated cells (t
= 131 min versus 16 min in apigenin- versus vehicle-treated cells, respectively). The mechanism of p53 protein stabilization is currently being investigated. To determine whether p53 was transcriptionally active, we also performed gel mobility shift assays and transient transfection studies using a luciferase plasmid under the control of the p21/waf1 promoter. Both p53 DNA-binding activity and transcriptional activation peaked after 24 h of exposure to apigenin. These studies suggest that apigenin may exert anti-tumorigenic activity by stimulating the p53–p21/waf1 response pathway.
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