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17beta-estradiol inhibits oxidative stress-induced apoptosis in keratinocytes by promoting Bcl-2 expression.

Authors
  • Kanda, Naoko
  • Watanabe, Shinichi
Type
Published Article
Journal
The Journal of investigative dermatology
Publication Date
Dec 01, 2003
Volume
121
Issue
6
Pages
1500–1509
Identifiers
PMID: 14675202
Source
Medline
License
Unknown

Abstract

We examined in vitro effects of 17beta-estradiol on H2O2-induced apoptosis in human keratinocytes. 17beta-estradiol prevented the H2O2-induced apoptosis. H2O2 decreased, whereas 17beta-estradiol increased Bcl-2 protein and mRNA levels in keratinocytes, and H2O2 plus 17beta-estradiol led to basal levels. Overexpression of Bcl-2 protected keratinocytes against H2O2-induced apoptosis, indicating the anti-apoptotic effect of Bcl-2. H2O2 suppressed, whereas 17beta-estradiol enhanced bcl-2 promoter activity, and H2O2 plus 17beta-estradiol led to basal activity. Cyclic adenosine monophosphate (cAMP) response element on bcl-2 promoter was responsible for the effects of 17beta-estradiol and H2O2. Bcl-2 expression was enhanced by membrane-impermeable bovine serum albumin-conjugated 17beta-estradiol, indicating the effects via membrane 17beta-estradiol-binding sites. H2O2 decreased, whereas 17beta-estradiol increased the amount of phosphorylated cAMP response element-binding protein and cAMP response element-dependent transcriptional activity, and H2O2 plus 17beta-estradiol led to basal levels. H-89, an inhibitor of cAMP-dependent protein kinase A, suppressed basal and 17beta-estradiol-induced cAMP response element-binding protein phosphorylation, cAMP response element-dependent transcriptional activity, Bcl-2 expression, and apoptosis resistance. The cAMP analog, dibutyryl cAMP, enhanced cAMP response element-binding protein phosphorylation, cAMP response element-dependent transcriptional activity, Bcl-2 expression, and apoptosis resistance. 17Beta-estradiol increased intracellular cAMP level and protein kinase A activity, whereas these were not altered by H2O2. Keratinocytes expressed mRNA for estrogen receptor beta and guanine nucleotide-binding protein-coupled receptor, GPR30. GPR30 anti-sense oligonucleotide did, but anti-sense estrogen receptor beta did not suppress 17beta-estradiol-induced cAMP signal, cAMP response element-binding protein phosphorylation, Bcl-2 expression, and apoptosis resistance. These results suggest that 17beta-estradiol may enhance Bcl-2 expression and prevent H2O2-induced apoptosis by phosphorylating cAMP response element-binding protein via cAMP/protein kinase A pathway in keratinocytes. These effects of 17beta-estradiol may be mediated via membrane GPR30.

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