MDM2 regulates estrogen receptor α and estrogen responsiveness in breast cancer cells

Kyounghyun Kim, Robert Burghardt, Rola Barhoumi, Syng ook Lee, Xinyi Liu, Stephen Safe

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

Murine double minute clone 2 (MDM2) is a multifunctional protein, which modulates nuclear receptor-mediated transactivation. In this study, we show that MDM2 significantly enhanced estrogen receptor α (ERα) and ERα/specificity protein-mediated transactivation in MCF-7 and ZR-75 breast cancer cells. This was demonstrated by both MDM2 overexpression and knockdown experiments by RNA interference. ERα interacted with wild-type MDM2 and deletion mutants of MDM2 containing amino acids 1-342 (C-terminal deletion) and 134-490 (N-terminal deletion), but not 134-342. In contrast, only wild-type but not mutant MDM2 enhanced ERα-mediated transactivation. Protein-protein interactions in vitro were 17b-estradiol (E2) independent, whereas resonance energy transfer experiments in living cells showed that E2 enhanced ERα-MDM2 interactions. Subsequent RNA interference and mammalian two-hybrid experiments suggested that MDM2 did not directly interact with endogenous coactivators such as the steroid receptor coactivators but played a role in enhancing ERα-mediating gene expression and estrogen responsiveness through interactions with ERα.

Original languageEnglish (US)
Pages (from-to)67-79
Number of pages13
JournalJournal of Molecular Endocrinology
Volume46
Issue number2
DOIs
StatePublished - Apr 2011

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

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