Selective binding of steroid receptors to octamer transcription factors determines transcriptional synergism at the mouse mammary tumor virus promoter: A molecular mechanism for transcription factor recruitment to promoter DNA.
|Title:||Selective binding of steroid receptors to octamer transcription factors determines transcriptional synergism at the mouse mammary tumor virus promoter: A molecular mechanism for transcription factor recruitment to promoter DNA.|
|Authors:||Préfontaine, Gratien G.|
|Abstract:||The glucocorticoid receptor (GR) and octamer transcription factors -1 and -2 (Oct -1/-2) function synergistically to activate gene transcription from the Mouse Mammary Tumor Virus (MMTV) promoter. Mechanisms responsible for the transcriptional synergy have not been characterized. I demonstrated a protein-protein interaction between rat GR and human Oct-1/-2 in vivo, and showed the interaction was sensitive to GR point mutations C500Y and L501P. This interaction correlated with the recruitment of Oct-l/-2 to promoter DNA and appeared to contribute at least in part to the transcriptional synergy observed. Based on this observation, a molecular mechanism was proposed that would be expected to restrict gene transcription to regulatory regions containing binding sites for both factors. The direct protein-protein interaction with GR and Oct-1/-2 mapped to the Octamer factor homeodomains suggesting the potential for a broadly based interaction for homeodomain proteins. Previously, in vitro binding studies had identified several nuclear hormone receptors with the potential to bind to the POU domain of octamer factors. However in vivo, only the GR, the progesterone receptor (PR) and the androgen receptor (AR) appeared to have the potential to interact with octamer factors physically and functionally through their DNA-binding and hinge domains. In contrast, the mineralocorticoid receptor (MR) failed to interact. These steroid receptors can activate transcription through common hormone response elements (HREs) but they perform distinct physiological functions by regulating unique target genes. In transient transfection assays, I demonstrated that these steroid receptors could activate transcription from the MMTV promoter to similar levels. However, differential modes of gene regulation were employed by individual steroid receptors. Transcription mediated by GR and PR was dependent on the octamer motifs while that mediated by MR and AR was octamer motif independent. The configuration of the MMTV HREs was restricted to GR- and PR-mediated transcription but octamer factor recruitment to DNA permitted gene transcription from the MMTV promoter. These results suggest that the configuration of the HREs on the MMTV promoter determine steroid receptor-specific transcriptional responses.|
|Collection||Thèses, 1910 - 2010 // Theses, 1910 - 2010|