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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Zearalenone is a naturally occurring estrogenic contaminant of moldy feeds and is present in high concentrations in dairy products and cereals. Zearalenone was postulated to contribute to the overall estrogen load of women, but the mechanisms of its action are not known. We demonstrated that zearalenone could stimulate the growth of estrogen receptor-positive human breast carcinoma cell line MCF-7. In addition, zearalenone functioned as an antiapoptotic agent by increasing the survival of MCF-7 cell cultures undergoing apoptosis caused by serum withdrawal. Treatment of these cells with 100 nM zearalenone induced cell-cycle transit after increases in the expression of c-myc mRNA and cyclins D1, A, and B1 and downregulation of p27(Kip-1). G(1)/G(2)-phase kinase activity and phosphorylation of the retinoblastoma gene product was also evident. Flow cytometric analysis demonstrated entry of cells into the S and G(2)/M phases of the cell cycle, and phosphorylation of histone H3 occurred 36 h after zearalenone treatment. Ectopic expression of a dominant-negative p21(ras) completely abolished the zearalenone-induced DNA synthesis in these cells, and the specific inhibitor PD98059 for mitogen/extracellular-regulated protein kinase kinase arrested S-phase entry induced by zearalenone. These data suggest that the mitogen-activated protein kinase signaling cascade is required for zearalenone's effects on cell-cycle progression in MCF-7 cells. Given the presence of this mycotoxin in cereals, milk, and meat, the possibility that zearalenone is a potential promoter of breast cancer tumorigenesis should be investigated further. Mol. Carcinog. 30:88-98, 2001.
Mol Carcinog 2001 Feb
PMID:Signal transduction through the Ras/Erk pathway is essential for the mycoestrogen zearalenone-induced cell-cycle progression in MCF-7 cells. 1124 56

Intron-bearing replacement histone H3 genes in Arabidopsis and other plants are highly and constitutively expressed. We demonstrate that the introns located within the 5'-untranslated regions (5'-UTR) of the two Arabidopsis replacement H3 genes will abolish the cell cycle dependence of an endogenous histone H4 promoter. We demonstrate that these introns, functionally combined with their endogenous promoters, could produce the high and constitutive expression of the replacement H3 genes observed in planta. They strongly increase gene expression whatever the promoter, from the strong 35S CaMV promoter to complete and resected promoters of cell cycle-dependent and replacement histone genes. Quantitative analysis of the extent of reporter gene enhancement in different parts of developing transgenic plantlets, ranging from 2-fold to 70-fold, supports the notion that trans-acting factors are responsible for this effect. Such factors appear most abundant in roots.
Plant Mol Biol 2001 Jan
PMID:Tissue-dependent enhancement of transgene expression by introns of replacement histone H3 genes of Arabidopsis. 1124 3

The growth suppressor promyelocytic leukemia protein (PML) is disrupted by the chromosomal translocation t(15;17) in acute promyelocytic leukemia (APL). PML plays a key role in multiple pathways of apoptosis and regulates cell cycle progression. The present study demonstrates that PML represses transcription by functionally and physically interacting with histone deacetylase (HDAC). Transcriptional repression mediated by PML can be inhibited by trichostatin A, a specific inhibitor of HDAC. PML coimmunoprecipitates a significant level of HDAC activity in several cell lines. PML is associated with HDAC in vivo and directly interacts with HDAC in vitro. The fusion protein PML-RARalpha encoded by the t(15;17) breakpoint interacts with HDAC poorly. PML interacts with all three isoforms of HDAC through specific domains, and its expression deacetylates histone H3 in vivo. Together, the results of our study show that PML modulates histone deacetylation and that loss of this function in APL alters chromatin remodeling and gene expression. This event may contribute to the development of leukemia.
Mol Cell Biol 2001 Apr
PMID:The growth suppressor PML represses transcription by functionally and physically interacting with histone deacetylases. 1125 76

The encapsulation of otherwise transcribable loci within transcriptionally inactive heterochromatin is rapidly gaining recognition as an important mechanism of epigenetic gene regulation. In the fission yeast Schizosaccharomyces pombe, heterochromatinization of the mat2/mat3 loci silences the mating-type information encoded within these loci. Here, we present the solution structure of the chromo domain from the cryptic loci regulator protein Clr4. Clr4 is known to regulate silencing and switching at the mating-type loci and to affect chromatin structure at centromeres. Clr4 and its human and Drosophila homologs have been identified as histone H3-specific methyltransferases, further implicating this family of proteins in chromatin remodeling. Our structure highlights a conserved surface that may be involved in chromo domain-ligand interactions. We have also analyzed two chromo domain mutants (W31G and W41G) that previously were shown to affect silencing and switching in full-length Clr4. Both mutants are significantly destabilized relative to wild-type.
J Mol Biol 2001 Mar 30
PMID:Solution structure, domain features, and structural implications of mutants of the chromo domain from the fission yeast histone methyltransferase Clr4. 1127 6

We analyzed the relationship between histone acetylation and transcriptional regulation at 40 Saccharomyces cerevisiae promoters that respond to specific activators and repressors. In accord with the general correlation between histone acetylation and transcriptional activity, Gcn4 and the general stress activators (Msn2 and Msn4) cause increased acetylation of histones H3 and H4. Surprisingly, Gal4-dependent activation is associated with a dramatic decrease in histone H4 acetylation, whereas acetylation of histone H3 is unaffected. A specific decrease in H4 acetylation is also observed, to a lesser extent, at promoters activated by Hap4, Adr1, Met4, and Ace1. Activation by heat shock factor has multiple effects; H4 acetylation increases at some promoters, whereas other promoters show an apparent decrease in H3 and H4 acetylation that probably reflects nucleosome loss or gross alteration of chromatin structure. Repression by targeted recruitment of the Sin3-Rpd3 histone deacetylase is associated with decreased H3 and H4 acetylation, whereas repression by Cyc8-Tup1 is associated with decreased H3 acetylation but variable effects on H4 acetylation; this suggests that Cyc8-Tup1 uses multiple mechanisms to reduce histone acetylation at promoters. Thus, individual activators confer distinct patterns of histone acetylation on target promoters, and transcriptional activation is not necessarily associated with increased acetylation. We speculate that the activator-specific decrease in histone H4 acetylation is due to blocking the access or function of an H4-specific histone acetylase such as Esa1.
Mol Cell Biol 2001 Apr
PMID:Histone acetylation at promoters is differentially affected by specific activators and repressors. 1128 52

Members of the heterochromatin protein 1 (HP1) family are silencing nonhistone proteins. Here, we show that in P19 embryonal carcinoma (EC) nuclei, HP1 alpha, beta, and gamma form homo- and heteromers associated with nucleosomal core histones. In vitro, all three HP1s bind to tailed and tailless nucleosomes and specifically interact with the histone-fold of histone H3. Furthermore, HP1alpha interacts with the linker histone H1. HP1alpha binds to H3 and H1 through its chromodomain (CD) and hinge region, respectively. Interestingly, the Polycomb (Pc1/M33) CD also interacts with H3, and HP1alpha and Pc1/M33 binding to H3 is severely impaired by CD mutations known to abrogate HP1 and Polycomb silencing in Drosophila. These results define a novel function for the conserved CD and suggest that HP1 self-association and histone binding may play a crucial role in HP1-mediated heterochromatin assembly.
Mol Cell 2001 Apr
PMID:Heterochromatin formation in mammalian cells: interaction between histones and HP1 proteins. 1133 97

The nature of the interaction of coactivator proteins with transcriptionally active promoters in chromatin is a fundamental question in transcriptional regulation by RNA polymerase II. In this study, we used a biochemical approach to examine the functional association of the coactivator p300 with chromatin templates. Using in vitro transcription template competition assays, we observed that p300 forms a stable, template-committed complex with chromatin during the transcription process. The template commitment is dependent on the time of incubation of p300 with the chromatin template and occurs independently of the presence of a transcriptional activator protein. In studies examining interactions between p300 and chromatin, we found that p300 binds directly to chromatin and that the binding requires the p300 bromodomain, a conserved 110-amino-acid sequence found in many chromatin-associated proteins. Furthermore, we observed that the isolated p300 bromodomain binds directly to histones, preferentially to histone H3. However, the isolated p300 bromodomain does not bind to nucleosomal histones under the same assay conditions, suggesting that free histones and nucleosomal histones are not equivalent as binding substrates. Collectively, our results suggest that the stable association of p300 with chromatin is mediated, at least in part, by the bromodomain and is critically important for p300 function. Furthermore, our results suggest a model for p300 function that involves distinct activator-dependent targeting and activator-independent chromatin binding activities.
Mol Cell Biol 2001 Jun
PMID:p300 forms a stable, template-committed complex with chromatin: role for the bromodomain. 1135 96

The ability of DNA-binding proteins to recognize their cognate sites in chromatin is restricted by the structure and dynamics of nucleosomal DNA, and by the translational and rotational positioning of the histone octamer. Here, we use six different pyrrole-imidazole polyamides as sequence-specific molecular probes for DNA accessibility in nucleosomes. We show that sites on nucleosomal DNA facing away from the histone octamer, or even partially facing the histone octamer, are fully accessible and that nucleosomes remain fully folded upon ligand binding. Polyamides only failed to bind where sites are completely blocked by interactions with the histone octamer. Removal of the amino-terminal tails of either histone H3 or histone H4 allowed these polyamides to bind. These results demonstrate that much of the DNA in the nucleosome is freely accessible for molecular recognition in the minor groove, and also support a role for the amino-terminal tails of H3 and H4 in modulating accessibility of nucleosomal DNA.
J Mol Biol 2001 Jun 08
PMID:Sequence-specific recognition of DNA in the nucleosome by pyrrole-imidazole polyamides. 1139 84

Although the cellular response to chemical-induced stress is relatively well characterized, particularly the response to DNA damage, factors that govern the outcome of the stress response (cell survival or cell death) are less clearly defined. In this context, the mitogen-activated protein kinase (MAPK) family responds to a variety of physical and chemical stresses. The activation of MAPKs, especially the extracellular-regulated protein kinase subfamily, seems to play a causal role in death of renal proximal tubular epithelial cells (LLC-PK1) induced by reactive oxygen species (ROS). In this study, we show that extracellular signal receptor-activated kinase (ERK) activation may be coupled with LLC-PK1 cell death via changes in chromatin structure, which is mediated by increases in the phosphorylation of histone H3 (a post-translational modification required for both chromosome condensation and segregation during mitosis) and premature chromatin/chromosomal condensation, leading to cell death. In support of this view, 2,3,5-tris-(glutathione-S-yl)hydroquinone (TGHQ)-induced phosphorylation of histone H3 is accompanied by increases in chromatin condensation, as observed with the use of 4,6-diamidino-2-phenylindole-fluorescent staining, and by decreases in the sensitivity of chromatin to digestion by micrococcal nuclease. Changes in chromatin structure precede cell death. TGHQ-induced histone H3 phosphorylation and chromatin condensation are inhibited by PD098059, which selectively inhibits MAPK kinase, an upstream regulator of ERKs. Moreover, histone phosphorylation is modulated by poly(ADP-)ribosylation. Thus, the inhibition of poly(ADP-ribose)polymerase with 3-aminobenzamide prevents histone H3 phosphorylation and increases cell survival, suggesting that ADP-ribosylation and histone H3 phosphorylation are coupled in this model of ROS-induced DNA damage and cell death. The coupling of histone phosphorylation with ribosylation has not been previously demonstrated.
Mol Pharmacol 2001 Aug
PMID:Histone H3 phosphorylation is coupled to poly-(ADP-ribosylation) during reactive oxygen species-induced cell death in renal proximal tubular epithelial cells. 1145 28

The relationship between DNA methylation and histone acetylation at the imprinted mouse genes U2af1-rs1 and Snrpn is explored by chromatin immunoprecipitation (ChIP) and resolution of parental alleles using single-strand conformational polymorphisms. The U2af1-rs1 gene lies within a differentially methylated region (DMR), while Snrpn has a 5' DMR (DMR1) with sequences homologous to the imprinting control center of the Prader-Willi/Angelman region. For both DMR1 of Snrpn and the 5' untranslated region (5'-UTR) and 3'-UTR of U2af1-rs1, the methylated and nonexpressed maternal allele was underacetylated, relative to the paternal allele, at all H3 lysines tested (K14, K9, and K18). For H4, underacetylation of the maternal allele was exclusively (U2af1-rs1) or predominantly (Snrpn) at lysine 5. Essentially the same patterns of differential acetylation were found in embryonic stem (ES) cells, embryo fibroblasts, and adult liver from F1 mice and in ES cells from mice that were dipaternal or dimaternal for U2af1-rs1. In contrast, in a region within Snrpn that has biallelic methylation in the cells and tissues analyzed, the paternal (expressed) allele showed relatively increased acetylation of H4 but not of H3. The methyl-CpG-binding-domain (MBD) protein MeCP2 was found, by ChIP, to be associated exclusively with the maternal U2af1-rs1 allele. To ask whether DNA methylation is associated with histone deacetylation, we produced mice with transgene-induced methylation at the paternal allele of U2af1-rs1. In these mice, H3 was underacetylated across both the parental U2af1-rs1 alleles whereas H4 acetylation was unaltered. Collectively, these data are consistent with the hypothesis that CpG methylation leads to deacetylation of histone H3, but not H4, through a process that involves selective binding of MBD proteins.
Mol Cell Biol 2001 Aug
PMID:DNA methylation is linked to deacetylation of histone H3, but not H4, on the imprinted genes Snrpn and U2af1-rs1. 1146 25


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