Convergence on chromatin of non-genomic and genomic pathways of hormone signaling
- 作者：Guillermo P. Vicent ; Cecilia Ballaré ; A. Silvina Nacht ; Jaime Clausell ; Alicia Subtil-Rodrí ; guez ; Ignacio Quiles ; Albert Jordan ; Miguel Beato
- 关键词：Mouse mammary tumour virus ; Progesterone receptor ; Chromatin ; Transcriptional regulation ; Histone H1 ; Kinases
- 刊名：The Journal of Steroid Biochemistry and Molecular Biology
- 出版年：2008
- 期刊代码：172_09600760
- 类别：med
- 出版时间：April 2008
- 卷：109
- 期：3-5
- 页码：344-349
- 文件大小：708 K
摘要
Gene regulation by steroid hormones involves genomic and non-genomic signaling pathways and the relationship between these two pathways is unknown. Genomic actions are often mediated by binding of the ligand-activated hormone receptors to hormone responsive elements (HREs) followed by recruitment of co-regulators, remodeling of chromatin and formation of the transcription initiation complex. The non-genomic effects of steroid hormones involve the rapid and transient activation of several kinase cascades often mediated by a subpopulation of “nuclear” receptors located in the cytoplasmic side of the cell membrane. The progesterone effect on breast cancer cell proliferation involves activation of the Src/Ras/Erk cascade mediated by a specific interaction between two domains of the N-terminal half of PR and the ligand-binding domain of ER
. Unexpectedly, selective inhibition of Erk, or its target kinase Msk1, interferes with chromatin remodeling and blocks MMTV transcriptional activation. A complex of activated PR, Erk and Msk1 is recruited to promoter already 5 min after hormone treatment and phosphorylates histone H3 at serine 10, leading to displacement of HP1γ, as a requisite for recruitment of Src1, chromatin remodeling complexes (hSnf2h and Brg1) and RNA polymerase II. Thus, activation of signaling cascades in the cytoplasm is essential for chromatin remodeling and transcriptional activation of a subset of steroid hormone target genes.
. Unexpectedly, selective inhibition of Erk, or its target kinase Msk1, interferes with chromatin remodeling and blocks MMTV transcriptional activation. A complex of activated PR, Erk and Msk1 is recruited to promoter already 5 min after hormone treatment and phosphorylates histone H3 at serine 10, leading to displacement of HP1γ, as a requisite for recruitment of Src1, chromatin remodeling complexes (hSnf2h and Brg1) and RNA polymerase II. Thus, activation of signaling cascades in the cytoplasm is essential for chromatin remodeling and transcriptional activation of a subset of steroid hormone target genes.