Upstream determinants of estrogen receptor-α regulation of metastatic tumor antigen 3 pathway

Sandip K. Mishra, Amjad H. Talukder, Anupama E. Gururaj, Zhibo Yang, Rajesh R. Singh, My G. Mahoney, Clara Francí, Ratna K. Vadlamudi, Rakesh Kumar

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

Abstract

Although recent studies have shown a role of estrogen receptor-α (ER) in the regulation of epithelial-to-mesenchymal transition via MTA3, the role of upstream determinants of ER regulation of MTA3 and the underlying molecular mechanism remains unknown. Here we show that MTA3 gene regulation by ER is influenced by dynamic changes in levels of nuclear coregulators. MTA3 promoter has a functional ER element half-site with which MTA1 and HDACs interact under basal conditions. Upon estrogen stimulation, these corepressors are derecruited with concomitant recruitment of ER, leading to increased MTA3 transcription and expression. Genetic inactivation of MTA1 pathway promotes the ability of ER to up-regulate MTA3 expression, whereas knockdown of ER enhances MTA1 association with MTA3 gene. Modulation of ER functions, by corepressors (i.e. MTA1 and MTA1s) or coactivators (i.e. AIB1 and PELP1/MNAR), alters ER recruitment to MTA3 chromatin, MTA3 transcription, and expression of downstream epithelial-to-mesenchymal transition components. These studies provide novel insights into the transregulation of the MTA3 gene and reveal novel roles of upstream determinants in modifying the outcome of MTA3 axis and cell differentiation.

Original languageEnglish (US)
Pages (from-to)32709-32715
Number of pages7
JournalJournal of Biological Chemistry
Volume279
Issue number31
DOIs
StatePublished - Jul 30 2004

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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