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  • Title: Activation of the prolactin gene by peroxisome proliferator-activated receptor-alpha appears to be DNA binding-independent.
    Author: Tolón RM, Castillo AI, Aranda A.
    Journal: J Biol Chem; 1998 Oct 09; 273(41):26652-61. PubMed ID: 9756906.
    Abstract:
    Although the effects of the peroxisome proliferator-activated receptors (PPARs) have been studied primarily in adipocytes and liver, the wide distribution of these receptors suggests that they might also play a role in other cell types. We present evidence that PPAR activators stimulate the expression of the prolactin gene in pituitary GH4C1 cells. Transfection assays in non-pituitary HeLa cells showed that stimulation of the prolactin promoter by PPARalpha requires the presence of the transcription factor GHF-1 (or Pit-1). Proximal promoter sequences confer responsiveness to PPARalpha, and activation by this receptor is lost concomitantly with the response to GHF-1. Surprisingly, expression of the retinoid X receptor (RXR) abolishes stimulation by PPARalpha. Furthermore, the promoter region that confers PPARalpha responsiveness does not contain a PPAR response element. This suggests that the transcriptional effect of PPARalpha might be mediated by protein-protein interactions rather than by binding of PPAR/RXR to the promoter. A direct interaction between PPARalpha and GHF-1 was confirmed by in vitro binding studies. Expression of the coactivators SRC-1 and CREB-binding protein, which bind to PPAR, also enhanced the responsiveness of the prolactin promoter to PPARalpha. Furthermore, CREB-binding protein also significantly increased activation by GHF-1, and both proteins associated in vitro. Thus, PPARalpha, a receptor that normally acts as a ligand-dependent transcription factor by binding to specific DNA sequences in one context, can also stimulate the prolactin promoter by association with GHF-1 and coactivator proteins.
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