The Journal of Steroid Biochemistry and Molecular Biology (original) (raw)
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Convergence on chromatin of non-genomic and genomic pathways of hormone signaling
The Journal of Steroid Biochemistry and Molecular Biology, 2008
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 HP1␥, 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.
Minireview: Role of Kinases and Chromatin Remodeling in Progesterone Signaling to Chromatin
Molecular Endocrinology, 2010
Steroid hormones regulate gene expression by interaction of their receptors with hormone-responsive elements on DNA or with other transcription factors, but they can also activate cytoplasmic signaling cascades. Rapid activation of Erk by progestins via an interaction of the progesterone receptor (PR) with the estrogen receptor is critical for transcriptional activation of the mouse mammary tumor virus (MMTV) promoter and other progesterone target genes. Erk activation leads to the phosphorylation of PR, activation of mitogen-and stress-activated protein kinase 1, and the recruitment of a complex of the three activated proteins and of P300/CBP-associated factor (PCAF) to a single nucleosome, resulting in the phosphoacetylation of histone H3 and the displacement of heterochromatin protein 1␥. Hormone-dependent gene expression requires ATP-dependent chromatin remodeling complexes. Two switch/sucrose nonfermentable-like complexes, Brahma-related gene 1-associated factor (BAF) and polybromo-BAF are present in breast cancer cells, but only BAF is recruited to the MMTV promoter and cooperates with PCAF during activation of hormone-responsive promoters. PCAF acetylates histone H3 at K14, an epigenetic mark recognized by BAF subunits, thus anchoring the complex to chromatin. BAF catalyzes localized displacement of histones H2A and H2B, facilitating access of nuclear factor 1 and additional PR complexes to the hidden hormone-responsive elements on the MMTV promoter. The linker histone H1 is a structural component of chromatin generally regarded as a general repressor of transcription. However, it contributes to a better regulation of the MMTV promoter by favoring a more homogeneous nucleosome positioning, thus reducing basal transcription and actually enhancing hormone induced transcription. During transcriptional activation, H1 is phosphorylated and displaced from the promoter. The kinase cyclin-dependent kinase 2 is activated after progesterone treatment and could catalyze progesterone-induced phosphorylation of histone H1 by chromatin remodeling complexes. The initial steps of gene induction by progestins involve changes in the chromatin organization of target promoters that require the activation of several kinase signaling pathways initiated by membrane anchored PR. Because these pathways also respond to other external signals, they serve to integrate the hormonal response in the global context of the cellular environment. (Molecular Endocrinology 24: 2088 -2098, 2010) NURSA Molecule Pages: Nuclear Receptors: PR ͉ GR ͉ ER␣; Corregulators: P/CAF ͉ BAF57 ͉ BRM ͉ BRG1 ͉ SRC-1 ͉ GRIP1 ͉ AIB1; Ligands: Progesterone ͉ Dexamethasone.
Molecular Cell, 2006
How genes are regulated in the context of chromatin is a central question of biology. Steroid hormones control gene expression via interaction of their receptors with target sequences on DNA but can also activate cytoplasmic signaling cascades. Here we report that rapid Erk activation by progestins participates in induction of target genes by preparing the chromatin for transcription. Five minutes after hormone treatment, Erk activation leads to phosphorylation of the progesterone receptor (PR), activation of Msk1, and recruitment of a complex of the three proteins to a nucleosome on the MMTV promoter. Msk1 phosphorylates histone H3, leading to displacement of HP1g and recruitment of Brg1 and RNA polymerase II. Cell-free experiments show a direct interaction between PR, Erk, and Msk1 and support the importance of H3 phosphorylation for nucleosome remodeling. Inhibition of Msk1 activation blocks recruitment of the kinase complex, H3 phosphorylation, and HP1g displacement, thus precluding remodeling and induction of the promoter.
Annals of the New York Academy of Sciences, 2006
Progesterone treatment of cultured cells carrying an integrated single copy of an MMTV transgene leads to recruitment of progesterone receptor (PR), SWI/SNF, and SNF2h-related complexes to MMTV promoter. Recruitment is accompanied by selective displacement of histones H2A and H2B from the nucleosome B. In nucleosomes assembled on promoter sequences, SWI/SNF displaces histones H2A and H2B from MMTV nucleosome B, but not from other MMTV nucleosomes or from an rDNA promoter nucleosome. Thus, the outcome of nucleosome remodeling by purified SWI/SNF depends on the DNA sequence. On the other hand, 5 min after hormone treatment, the cytoplasmic signaling cascade Src/Ras/Erk is activated via an interaction of PR with the estrogen receptor, which activates Src. As a consequence of Erk activation PR is phosphorylated, Msk1 is activated, and a ternary complex PR-Erk-Msk1 is recruited to MMTV nucleosome B. Msk1 phosphorylates H3 at serine 10, which is followed by acetylation at lysine 14,
Transcription, 2017
How genes are repressed by steroid hormones remains a matter of debate, and several indirect mechanisms have been proposed. We found that the ligand-activated progesterone receptor recruits to the promoter of downregulated genes a repressor complex composed of HP1γ, the lysine demethylase LSD1, histone deacetylases, coREST, the RNA SRA, and the ATPase BRG1. BRG1 is needed for chromatin remodeling and facilitates the deposition of linker histone variant H1.2, which compacts chromatin and hinders RNA polymerase loading and transcription. Thus, steroid hormone receptors can repress genes in ways reminiscent of those used for gene induction, namely by directly targeting factors that remodel chromatin. But while PR-dependent gene induction in T47D cells is mainly achieved by potentiating enhancer activity, repression acts at the level of gene promoters.
Molecular and Cellular Endocrinology, 2012
Gene regulation requires access of transcription factors to DNA sequences of target genes, which is limited by the compaction of DNA in chromatin. Based on our studies on the Progesterone receptor (PR)dependent hormonal induction of mouse mammary tumor virus (MMTV) promoter we found that remodeling of the various levels of chromatin organization is a complex and necessary prerequisite for regulation. Two consecutive cycles are essential for transcriptional activation, both involving the collaboration between activated protein kinases, histone modifying enzymes and ATP-dependent chromatin remodelers. The first cycle ends with the displacement of histone H1 and decompaction of higher order chromatin structure. The second cycle leads to the displacement of dimers of histones H2A and H2B resulting in opening of nucleosomes. In both cases the hormone receptor recruits an ATP-dependent chromatin remodeler, whose binding to chromatin is stabilized by distinct histone modifications. The final result is to facilitate full occupancy of the cis regulatory sites and access for the basal transcription machinery. Thus, activation of PR-target genes involves a very rapid coordination of enzymatic activities via crosstalk with various kinase-signaling pathways.
Transcriptional control by steroid hormones
The Journal of Steroid Biochemistry and Molecular Biology, 1992
Smmnary--Gene regulation by steroid hormones leads to induction or repression of particular sets of genes. These effects are mediated by intracellular hormone receptors that, in the unliganded state, are maintained in an inactive form by unknown mechanisms possibly involving association with other cellular proteins. Induction of the mouse mammary tumor virus (MMTV) requires binding of the hormone receptor to a complex hormone-responsive element (HRE) located between 75 and 190 bp upstream from the start of transcription. The interaction of several receptor molecules with the four receptor binding sites in the HRE is highly cooperative on circular DNA molecules and each individual site is needed for optimal induction. In chromatin the HRE is precisely organized in phased nucleosomes. Following hormone treatment and receptor binding, changes in chromatin structure are detected that correlate with binding of transcription factors, including nuclear factor I, to the MMTV promoter. However, though nuclear factor I acts as a basal transcription factor on the MMTV promoter it does not cooperate with the hormone receptors in terms of binding to free DNA, and mutation of the nuclear factor I binding site does not eliminate hormonal stimulation. This residual induction is mediated by octamer motifs, upstream of the TATA box, that bind the ubiquitous transcription factor OTF-1. Mutation of these octamer motifs does not influence basal transcription in vitro, but completely abolishes the stimulatory effect of progesterone receptor.
Two Chromatin Remodeling Activities Cooperate during Activation of Hormone Responsive Promoters
PLoS Genetics, 2009
Steroid hormones regulate gene expression by interaction of their receptors with hormone responsive elements (HREs) and recruitment of kinases, chromatin remodeling complexes, and coregulators to their target promoters. Here we show that in breast cancer cells the BAF, but not the closely related PBAF complex, is required for progesterone induction of several target genes including MMTV, where it catalyzes localized displacement of histones H2A and H2B and subsequent NF1 binding. PCAF is also needed for induction of progesterone target genes and acetylates histone H3 at K14, an epigenetic mark that interacts with the BAF subunits by anchoring the complex to chromatin. In the absence of PCAF, full loading of target promoters with hormone receptors and BAF is precluded, and induction is compromised. Thus, activation of hormone-responsive promoters requires cooperation of at least two chromatin remodeling activities, BAF and PCAF.
Epigenetic regulation of nuclear steroid receptors
Biochemical Pharmacology, 2006
b i o c h e m i c a l p h a r m a c o l o g y 7 2 ( 2 0 0 6 ) 1 5 8 9 -1 5 9 6 Estrogen receptor Peroxisome proliferator activated receptor Epigenetics Histone Abbreviations: NR, nuclear receptor AR, androgen receptor ERa, estrogen receptor PPARg, peroxisome proliferatoractivated receptor g HAT, histone acetyltransferase HDAC, histone deacetylase SRC, steroid receptor coactivator N-CoR, nuclear receptor corepresssor SMRT, silencing mediator of retinoid and thyroid hormone receptor TSA, trichostatin A SIRT1, Sirtuin 1 CBP, CREB binding protein p/CAF, p300/CBP-associated factor DNMT, DNA methyltransferase a b s t r a c t