Insulin-activated Elk-1 recruits the TIP60/NuA4 complex to increase prolactin gene transcription

  • Mahajan M
  • Stanley F
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Abstract

Insulin increases prolactin gene expression in GH4 cells through phosphorylation of Elk-1 ( Jacob and Stanley, 2001). We preformed a reverse two-hybrid screen using Elk-1-B42 as bait to identify proteins from GH4 cells that might serve as co-activators or co-repressors for insulin-increased prolactin gene expression. A number of the components of the TIP60/NuA4 complex interacted with Elk-1 suggesting that Elk-1 might activate transcription by recruiting the TIP60 chromatin-remodeling complex to the prolactin promoter. Inhibition of insulin-increased prolactin-luciferase expression by wild type and mutant adenovirus E1A protein provided physiological context for these yeast studies. Inhibition of histone deacetylases dramatically increased both basal and insulin-increased prolactin gene transcription. Co-immune precipitation experiments demonstrated Elk-1 and TIP60 associate in vitro. Transient or stable expression of TIP60 activated insulin-increased prolactin gene expression while a mutated TIP60 blocked insulin-increased prolactin gene expression. Analysis of the prolactin mRNA by quantitative RT-PCR showed that insulin-increased prolactin mRNA accumulation and that this was inhibited in GH4 cells that stably expressed mutant TIP60. Finally, ChIP experiments demonstrate the insulin-dependent occupancy of the prolactin promoter by Elk-1 and TIP60. Our studies suggest that insulin activates prolactin gene transcription by activating Elk-1 that recruits the NuA4 complex to the promoter. © 2013 .

Author-supplied keywords

  • Chromatin-remodeling
  • Elk-1
  • Insulin
  • Prolactin
  • TIP60
  • Transcription

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Authors

  • Muktar A. Mahajan

  • Frederick M. Stanley

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