β-Estradiol-dependent activation of the JAK/STAT pathway requires p/CIP and CARM1

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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.

Highlights

► p/CIP/CARM1 complex binds 204 proximal promoters in response to E2 in MCF-7 cells. ► Many p/CIP/CARM1 complex target genes have been implicated in cancer. ► 20% of target genes are transcriptionally altered following 12 h E2-stimulation ► Jak2 is a p/CIP/CARM1 complex target gene that is transcriptionally activated by E2 ► Chromatin modifications at Jak2 promoter support transcriptional permissiveness

Keywords

Cancer
Estrogen
pCIP/CARM1
Coactivator
Chromatin

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