title: β-Estradiol-dependent activation of the JAK/STAT pathway requires p/CIP and CARM1.
abstract: The steroid receptor coactivator p/CIP, also known as SRC-3, is an oncogene commonly amplified in breast and ovarian cancers. p/CIP is known to associate with coactivator arginine methyltransferase 1 (CARM1) on select estrogen responsive genes. We have shown, using a ChIP-on-chip approach, that in response to stimulation with 17β-estradiol (E2), the p/CIP/CARM1 complex is recruited to 204 proximal promoters in MCF-7 cells. Many of the complex target genes have been previously implicated in signaling pathways related to oncogenesis. Jak2, a member of the Jak/Stat signaling cascade, is one of the direct E2-dependent targets of the p/CIP/CARM1 complex. Following E2-treatment, histone modifications at the Jak2 promoter are reflective of a transcriptionally permissive gene, and modest changes in RNA and protein expression lead us to suggest that an additional factor(s) may be required for a more notable transcriptional and functional response. Bioinformatic examination of the 204 proximal promoter sequences of p/CIP/CARM1 targets supports the idea that transcription factor crosstalk is likely the favored mechanism of E2-dependent p/CIP/CARM1 complex recruitment. This data may have implications towards understanding the oncogenic role of p/CIP in breast cancer and ultimately allow for the identification of new prognostic indicators and/or viable therapeutic targets.
authors: Dept. of Oncology, The University of Western Ontario, Canada.
authors: N
authors: N
authors: Coughlan
authors: G
authors: G
authors: Thillainadesan
authors: J
authors: J
authors: Andrews
authors: M
authors: M
authors: Isovic
authors: J
authors: J
authors: Torchia
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism*; D002843:Chromatin / Q000235:genetics; D047369:Chromatin Immunoprecipitation; D004958:Estradiol / Q000494:pharmacology*; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006162:Guanylate Cyclase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D053613:Janus Kinase 1 / Q000235:genetics / Q000378:metabolism*; D056921:Nuclear Receptor Coactivator 3 / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; D053468:CARD Signaling Adaptor Proteins; D002843:Chromatin; D004967:Estrogens; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D004958:Estradiol; C538866:NCOA3 protein, human; D056921:Nuclear Receptor Coactivator 3; C507904:JAK1 protein, human; D053613:Janus Kinase 1; C426242:CARD11 protein, human; D006162:Guanylate Cyclase