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		<p>Steroid hormone receptors are transcription<lb/> factors that regulate transcription in
			an exqui-<lb/>site manner <ref type="biblio">1</ref> . In the absence of ligand,
			hormone<lb/> receptors either remain inactive in the cyto-<lb/>plasm or repress promoter
			activity through the<lb/> recruitment of co-repressors, including histone<lb/>
			deacetylase enzymes (HDACs). Co-repressors<lb/> are dislodged by ligand binding and
			hormone<lb/> receptors then initiate promoter activation<lb/> through the recruitment of
			co-activator com-<lb/>plexes that possess histone acetyltransferase<lb/> and
			chromatin-remodelling activities. Cycles<lb/> of acetylation and deacetylation at
			histone<lb/> tails are among the many dynamic covalent<lb/> modifications that
			nucleosomes endure <ref type="biblio">2</ref> .<lb/> Phosphorylation, ubiquitination,
			methylation,<lb/> sumoylation and ADP-ribosylation also occur<lb/> on several histone
			tail residues and are linked<lb/> closely with the transcriptional activity of many<lb/>
			promoters. It has also been suggested that such<lb/> modifications convey epigenetic
			information.<lb/> Steroid hormone receptors have served as a<lb/> model for the
			functional interplay between<lb/> transcription factors and their corresponding<lb/>
			chromatin-modifying transcriptional co-acti-<lb/>vators or co-repressors. Indeed, recent
			stud-<lb/>ies have documented the interaction of such<lb/> receptors with a number of
			enzymes capable<lb/> of modifying histone tails in both normal <ref type="biblio"
				>3</ref> and<lb/> pathological states <ref type="biblio">4</ref> .<lb/></p>

		<p>Many of the histone modifications have been<lb/> studied in detail; however, very little
			is known<lb/> about the biological function of histone H3<lb/> Thr 11 (H3T11)
			phosphorylation. Early stud-<lb/>ies in plant and mammalian cells suggested that<lb/>
			phosphorylation of H3T11 might be involved<lb/> in chromosome condensation during
			mitosis<lb/> and meiosis <ref type="biblio">5</ref> . On page 53 of this issue,
			Metzger<lb/> et al. <ref type="biblio">6</ref> demonstrate that H3T11
			phosphoryla-<lb/>tion is linked to transcriptional regulation in<lb/> response to
			stimulation with androgen receptor<lb/> agonists. The protein-kinase-C-related
			kinase<lb/> 1 (PRK1) is required for androgen-receptor-<lb/>dependent gene transcription
				<ref type="biblio">7</ref> . Interestingly,<lb/> the authors show that inhibition of
			PRK1<lb/> (either with the specific inhibitor Ro318220 or<lb/> by stable RNA
			interference-mediated silencing)<lb/> prevents androgen-receptor-mediated H3T11<lb/>
			phosphorylation at the promoter of prostate-<lb/>specific antigen (PSA). Analysis of the
			PSA<lb/> promoter has important implications, as aber-<lb/>rant regulation of PSA has
			not only been asso-<lb/>ciated with a large number of human prostate<lb/> tumours but
			also serves as an early marker for<lb/> diagnosis of prostate cancer. Metzger et al.
			show<lb/> that in prostate tumour cells, androgen recep-<lb/>tors interact directly with
			PRK1 and occupy the<lb/> same region on the PSA promoter. Indeed, the<lb/> presence of
			PRK1 is strictly required for H3T11<lb/> phosphorylation. In addition, PRK1 is able
			to<lb/> phosphorylate H3T11 in vitro.<lb/></p>

		<p>In a previous study, the histone demethylases<lb/> LSD1 and JMJD2C were shown to
			participate<lb/> in androgen-receptor-dependent transcription<lb/> in a coordinated
			fashion <ref type="biblio">8</ref> . These authors have<lb/> extended their analyses to
			show that phosphor-<lb/>ylation of H3T11 facilitates Lys 9 (K9) demeth-<lb/>ylation by
			the demethylase JMJD2C (Jumonji C<lb/> (JmjC) domain-containing protein). One
			inter-<lb/>pretation of these results is that trimethylated<lb/> K9-containing
			nucleosomes are better sub-<lb/>strates for JMJD2C when H3T11 is phosphor-<lb/>ylated.
			Alternatively, PRK1 may phosphorylate<lb/> JMJD2C directly to enhance its
			demethylation<lb/> activity. As H3K9 trimethylation (a docking<lb/> site for an
			important component of hetero-<lb/>chromatin, heterochromatin protein 1 (HP1;<lb/>
			<ref type="biblio">refs 9, 10</ref>)) has been correlated closely with<lb/>
			transcriptional repression, reduced levels of<lb/> trimethyl K9 caused by H3T11
			phosphoryla-<lb/>tion may lead to transcriptional activation.<lb/></p>

		<p>Enhancement of H3K9 demethylation<lb/> accounts for only part of the effects of
			PRK1/<lb/> H3T11 phosphorylation in regulating pro-<lb/>moter activity. Metzger et al.
			provide additional<lb/> data correlating PRK1 occupancy at target pro-<lb/>moters with
			the activation of the transcription<lb/> complex from a pre-initiation to an
			initiation<lb/> state, as measured by phosphorylation of the<lb/> RNA polymerase II at
			Ser 5. Impairment of<lb/> PRK1 activity prevents Ser 5 phosphorylation<lb/> but not the
			recruitment of RNA polymerase<lb/> II to the promoter, suggesting a provocative<lb/>
			crosstalk between H3T11 phosphorylation,<lb/> H3K9 demethylation and the critical
			switch<lb/> from a pre-initiation to initiation complex.<lb/></p>

		<p>Although it seems that androgen receptors,<lb/> together with PRK1, fine-tune gene
			regulation,<lb/> it is not clear how ligands of androgen receptors<lb/> activate the Rho
			signalling pathways known to<lb/> control PRK1 activation or whether there is<lb/>
			cross-talk between ligands and Rho GTPases<lb/> at the plasma membrane. In a recent
			study<lb/> demonstrating that progestins trigger the cyto-<lb/>plasmic Src/Ras/Erk/Msk1
			signalling cascade,<lb/> Vicent et al. describe a model for
			progesterone-<lb/>receptor-mediated mouse mammary tumour<lb/> virus (MMTV) promoter
			activation <ref type="biblio">11</ref> . When a<lb/> ligand binds to the androgen
			receptor, Erk and<lb/> Msk1 navigate to promoters together with pro-<lb/>gesterone
			receptors. At the promoters, binding<lb/> of the Msk1–progesterone receptor complex<lb/>
			causes Msk1-dependent phosphorylation of<lb/> H3K10, HP1 displacement, RNA
			polymerase<lb/> II recruitment and activation of transcription.<lb/> Both Metzger et al.
			and Vicent et al. analysed<lb/> histone phosphorylation in response to hor-<lb/>mone
			stimulation; however, their findings<lb/> suggest that the consequence of such
			phospho-<lb/>rylation on transcriptional regulation differs<lb/></p>

		<figure>a<lb/> b<lb/> c<lb/> d<lb/> ON<lb/> PRK1<lb/> ?<lb/> KDM<lb/> PSA<lb/> AR<lb/>
			AR<lb/> Ligand<lb/> Signal<lb/> cascade<lb/> OFF<lb/> PSA<lb/> OFF<lb/> PRK1<lb/>
			AR<lb/> PSA<lb/> OFF<lb/> PRK1<lb/> KDM<lb/> AR<lb/> PRK1<lb/> RNA Polymerase II<lb/> =
			H3K9 tri-methylation<lb/> = CTD-S5 phosphorylation<lb/> = H3T11 phosphorylation<lb/> =
			Histone core<lb/></figure>

		<p>for the two hormone receptors. Thus, proges-<lb/>terone-receptor-mediated H3S10
			phosphoryla-<lb/>tion leads to release of HP1; in contrast, Metzger<lb/> et al. suggest
			that phosphorylation of H3T11<lb/> enhances demethylation. Even so, could PRK1<lb/> also
			be recruited in the cytoplasm and trans-<lb/>located to the nucleus by androgen
			receptors?<lb/> Moreover, given the cyclic activation of genes<lb/> regulated by
			hormones <ref type="biblio">12</ref> , how is phosphoryla-<lb/>tion of H3T11 reversed?
			One could envision a<lb/> direct recruitment of a protein phosphatase, as<lb/> has been
			suggested by studies in plants show-<lb/>ing that PP2A and PP1 phosphatases might
			be<lb/> involved in such a process <ref type="biblio">5</ref> .<lb/></p>

		<p>Although uncovering a new mode of regu-<lb/>lation for the PSA gene has potential
			clinical<lb/> implications, it is unclear at present whether<lb/> other genes targeted
			by androgen receptors are<lb/> phosphorylated at H3T11 after ligand admin-<lb/>istration
			and whether other steroid hormone<lb/> receptors would regulate transcription in a<lb/>
			similar manner.<lb/></p>

		<p>Finally, Metzger et al. show that high levels<lb/> of PRK1 and H3T11 phosphorylation
			exist<lb/> in early-stage prostate carcinomas, where<lb/> androgen receptors are known
			to be crucial<lb/> in controlling cell growth. The authors also<lb/> show that knockdown
			of PRK1 in prostate<lb/> tumour cells markedly reduces cellular<lb/> proliferation. They
			thus identify PRK1 as a<lb/> promising target for therapeutic interven-<lb/>tion in
			tumours where androgen receptors,<lb/> and possibly other steroid hormone
			recep-<lb/>tors, may be aberrantly regulating gene<lb/> expression.<lb/></p>

		<figure>Figure 1 Schematic representation depicting the sequence of events following
			association of androgen<lb/> receptors (AR) with PRK1. (a) Ligand-binding stimulates the
			association of AR with PRK1. (b) AR–PRK1<lb/> interaction causes phosphorylation of
			H3T11.(c) Demethylation of H3K9 by a lysine demethylase<lb/> (KDM) is enhanced. (d)
			Phosphorylation of RNA polymerase II on Ser 5 activates transcription.</figure>


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