Transcriptional synergism on the pS2 gene promoter between a p160 coactivator and estrogen receptor-alpha depends on the coactivator subtype, the type of estrogen response element, and the promoter context.
The pS2 gene is estrogen responsive in hepatocarcinoma cells (HepG2) in the presence of estrogen receptor alpha (ERalpha). The estrogenic activity is mediated through an estrogen response element (ERE) in the 5'-flanking region of the pS2 gene; however, an activator protein 1 (AP1) response element located close to the ERE in the pS2 promoter has also proven essential for a maximum response to estrogen. In the present study, we show estrogen-induced synergistic activity by the p160 coactivator steroid receptor coactivator-1 (SRC-1), mediated via the ERE and the AP1 response element in the pS2 promoter. In addition, we present data that support an interaction between the ERE and the AP1 motif via SRC-1. The related but distinct p160 coactivator, transcriptional intermediary factor-2, was a more potent activator of pS2 gene expression. In addition, transcriptional intermediary factor-2 was less dependent on an intact AP1 response element in the pS2 promoter than SRC-1. Furthermore, the type of ERE in the pS2 promoter influenced the potentiation by SRC-1, supported by less dependence on the AP1 motif when the natural ERE was substituted for by a consensus ERE. These results highlight several mechanisms whereby fine-tuning of estrogen responsiveness of an individual gene may be achieved.
Barkhem
Tomas
T
Karo Bio AB, Novum, S-141 57 Huddinge, Sweden. tomas.barkhem@karobio.se
Haldosén
Lars-Arne
LA
Gustafsson
Jan-Ake
JA
Nilsson
Stefan
S
D001483:Base Sequence; D006528:Carcinoma, Hepatocellular; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D003001:Cloning, Molecular; D004268:DNA-Binding Proteins; D047628:Estrogen Receptor alpha; D004967:Estrogens / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D029543:Nucleocytoplasmic Transport Proteins; D053766:Presenilin-2; D011401:Promoter Regions, Genetic; D016601:RNA-Binding Proteins; D011960:Receptors, Estrogen / Q000235:genetics* / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D014157:Transcription Factors; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D047628:Estrogen Receptor alpha; D004967:Estrogens; C491719:MYBBP1A protein, human; D008565:Membrane Proteins; D009687:Nuclear Proteins; D029543:Nucleocytoplasmic Transport Proteins; C508861:PSEN2 protein, human; D053766:Presenilin-2; D016601:RNA-Binding Proteins; D011960:Receptors, Estrogen; D011994:Recombinant Proteins; D014157:Transcription Factors