Activation of the p38 mitogen-activated protein kinase pathway by estrogen or by 4-hydroxytamoxifen is coupled to estrogen receptor-induced apoptosis

Chengcheng Zhang, David J. Shapiro

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17β-Estradiol (E2) or the antiestrogen, 4-hydroxytamoxifen (OHT), induce apoptosis in stably transfected estrogen receptor (ER)-positive HeLa- ER5 cells, p38 mitogen-activated protein kinase is implicated in cellular processes involving apoptosis. The p38 kinase inhibitor, SB203580, partially protects HeLa-ER5 cells against apoptosis induced by E2 or by OHT. E2 induces the p38 pathway 12-36-fold in ER-positive cell lines, while OHT induces p38 activity 2-5-fold. In an ER-positive cell line selected for resistance to E2-induced apoptosis, E2 no longer induced p38, and the ER no longer bound to the estrogen response element, while OHT induced both p38 and apoptosis. In cells selected for resistance to OHT-induced apoptosis, OHT no longer induced p38, while E2 induced p38 and apoptosis, and transactivated an estrogen response element-containing reporter gene. In MCF-7 cells, whose growth is stimulated by estrogen, E2 did not induce p38 or apoptosis, while OHT induced both p38 and apoptosis, and SB203580 protected against OHT- induced apoptosis. This work shows that E2 and OHT activate the p38 pathway, suggests that they use different pathways for p38 activation, and links activation of the p38 pathway to apoptosis induced by E2 and by OHT.

Original languageEnglish (US)
Pages (from-to)479-486
Number of pages8
JournalJournal of Biological Chemistry
Issue number1
StatePublished - Jan 7 2000


ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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