Protein Phosphatase 2A Activity Affects Histone H3 Phosphorylation and Transcription in <i>Drosophila melanogaster</i>

Nowak, Scott J.; Pai, Chi-Yun; Corcés, Victor G.

doi:10.1128/mcb.23.17.6129-6138.2003

Cited by 98 publications

(83 citation statements)

References 49 publications

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“…In Drosophila, targeting of heat shock-induced histone H3-phosphorylation to responsive loci is partly mediated by inhibiting PP2A phosphatase at responsive loci (Nowak et al, 2003) (reviewed in Dyson et al, 2005). There is also evidence that temporal differences in Aurora-B-mediated histone H3-S10 and H3-S28 phosphorylation during entry into mitosis are caused by PP1 phosphatase acting on S28 (but not S10) during late G2 phase (Goto et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

MAP kinase-mediated phosphorylation of distinct pools of histone H3 at S10 or S28 via mitogen- and stress-activated kinase 1/2

Dyson

Thomson

Inagaki

et al. 2005

Journal of Cell Science

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ERK and p38 MAP kinases, acting through the downstream mitogen- and stress-activated kinase 1/2 (MSK1/2), elicit histone H3 phosphorylation on a subfraction of nucleosomes – including those at Fos and Jun – concomitant with gene induction. S10 and S28 on the H3 tail have both been shown to be phospho-acceptors in vivo. Both phospho-epitopes appear with similar time-courses and both occur on H3 tails that are highly sensitive to TSA-induced hyperacetylation, similarities which might suggest that MSK1/2 phosphorylates both sites on the same H3 tails. Indeed, on recombinant histone octamers in vitro, MSK1 efficiently phosphorylates both sites on the same H3 tail. However, sequential immunoprecipitation studies show that antibodies against phosphorylated S10-H3 recover virtually all this epitope without depletion of phosphorylated S28-H3, and vice versa, indicating that the two phospho-epitopes are not located on the same H3 tail in vivo. Confocal immunocytochemistry confirms the clear physical separation of the two phospho-epitopes in the intact mouse nucleus. Finally, we used transfection-based experiments to test models that might explain such differential targeting. Overexpression and delocalisation of MSK1 does not result in the breakdown of targeting in vivo despite the fact that the ectopic kinase is fully activated by external stimuli. These studies reveal a remarkable level of targeting of S10 and S28 phosphorylation to distinct H3 tails within chromatin in the interphase mouse nucleus. Possible models for such exquisite targeting are discussed.

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Section: Discussionmentioning

confidence: 99%

MAP kinase-mediated phosphorylation of distinct pools of histone H3 at S10 or S28 via mitogen- and stress-activated kinase 1/2

Dyson

Thomson

Inagaki

et al. 2005

Journal of Cell Science

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“…To explain some of the changes in histone posttranslational modification in BAF-overexpressing cells, we hypothesized BAF might interact with and potentially recruit, specific chromatin regulators. Potential interactors from our BAF proteome 42 included HDAC1 and/or HDAC2 (distinguishing peptides not found), SET/I2PP2A (blocks H3-S10 dephosphorylation) 55 and G9a, an H3-K9 methyltransferase that generates the H3-K9-Me2 mark. 56 We therefore tested potential association with HDAC1, SET/I2PP2A or G9a and also tested for potential associations with histone acetyltransferases (HATs) or Aurora B (phosphorylates H3-S10 and H3-S28 during mitosis), 6 as controls for the observed changes in histone acetylation and phosphorylation.…”

Section: Resultsmentioning

confidence: 99%

Barrier-to-Autointegration Factor influences specific histone modifications

Andreassen

Wilson

2011

Nucleus

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Defects in the nuclear envelope or nuclear 'lamina' networks cause disease and can perturb histone posttranslational (epigenetic) regulation. Barrier-to-Autointegration Factor (BAF) is an essential but enigmatic lamina component that binds lamins, LEM-domain proteins, DNA and histone H3 directly. We report that BAF copurified with nuclease-digested mononucleosomes and associated with modified histones in vivo. BAF overexpression significantly reduced global histone H3 acetylation by 18%. In cells that stably overexpressed BAF 3-fold, silencing mark H3-K27-Me1/3 and active marks H4-K16-Ac and H4-Ac5 decreased significantly. Significant increases were also seen for silencing mark H3-K9-Me3, active marks H3-K4-Me2, H3-K9/K14-Ac and H4-K5-Ac and a mark (H3-K79-Me2) associated with both active and silent chromatin. Other increases (H3-S10-P, H3-S28-P and silencing mark H3-K9-Me2) did not reach statistical significance. BAF overexpression also significantly influenced cell cycle distribution. Moreover, BAF associated in vivo with SET/I2PP2A (protein phosphatase 2A inhibitor; blocks H3 dephosphorylation) and G9a (H3-K9 methyltransferase), but showed no detectable association with HDAC1 or HATs. These findings reveal BAF as a novel epigenetic regulator and are discussed in relation to BAF deficiency phenotypes, which include a hereditary progeria syndrome and loss of pluripotency in embryonic stem cells.

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“…In response to heat shock, transcriptionally active heat shock loci show a dramatic accumulation of H3S10ph marks, whereas global histone H3 phosphorylation decreases (71). Interestingly, Drosophila PP2A mutants display reduced H3 dephosphorylation at non-heat-shock genes during heat shock (56).…”

Section: Map Kinase Activation Sensitizes Resting Cells To Hdacmentioning

confidence: 99%

“…Genetic studies in Drosophila suggest a role for PP2A in the regulation of heat shock-regulated genes, which is linked to histone H3 phosphorylation (56,57). We, therefore, asked whether PP2A would play a role in the control of dynamic histone H3 phosphorylation and p21 gene expression in mammalian cells.…”

Section: Expression Of P21 Is Activated By Inducers Of the Mitogenactmentioning

confidence: 99%

A Phosphorylation Switch Regulates the Transcriptional Activation of Cell Cycle Regulator p21 by Histone Deacetylase Inhibitors

Simboeck

Sawicka

Zupkovitz

et al. 2010

Journal of Biological Chemistry

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Histone deacetylase inhibitors induce cell cycle arrest and apoptosis in tumor cells and are, therefore, promising anticancer drugs. The cyclin-dependent kinase inhibitor p21 is activated in histone deacetylase (HDAC) inhibitor-treated tumor cells, and its growth-inhibitory function contributes to the anti-tumorigenic effect of HDAC inhibitors. We show here that induction of p21 by trichostatin A involves MAP kinase signaling. Activation of the MAP kinase signaling pathway by growth factors or stress signals results in histone H3 serine 10 phosphorylation at the p21 promoter and is crucial for acetylation of the neighboring lysine 14 and recruitment of activated RNA polymerase II in response to trichostatin A treatment. In non-induced cells, the protein phosphatase PP2A is associated with the p21 gene and counteracts its activation. Induction of p21 is linked to simultaneous acetylation and phosphorylation of histone H3. The dual modification mark H3S10phK14ac at the activated p21 promoter is recognized by the phospho-binding protein 14-3-3, which protects the phosphoacetylation mark from being processed by PP2A. Taken together we have revealed a cross-talk of reversible phosphorylation and acetylation signals that controls the activation of p21 by HDAC inhibitors and identify the phosphatase PP2A as chromatin-associated transcriptional repressor in mammalian cells.Post-translational modifications of histones, such as acetylation, methylation, phosphorylation, and sumoylation play important roles in the regulation of chromatin accessibility and gene expression. The transformation of a differentiated resting cell into a highly proliferative tumor cell is accompanied by a severe change of the gene expression profile, which in turn is the direct consequence of acquired/accumulated tumor suppressor and oncogene mutations. In addition to these genetic alterations, epigenetic alterations are also involved in the development of cancer. These include covalent post-translational modifications of histones and changes in the methylation status of cytosines within CpG islands (1, 2). Therefore, compounds that target these epigenetic changes are of potential interest for anti-tumor therapies. Indeed, histone deacetylase (HDAC) 5 inhibitors have been shown to induce cell cycle arrest, differentiation, or apoptosis in tumor cells and are, therefore, promising anti-tumor drugs (3-5).One of the genes that is activated by different HDAC inhibitors encodes the cyclin-dependent kinase (CDK) inhibitor p21 cip1/waf1 (referred to as p21 thereafter) (3, 4). The p21 protein is a member of the CIP/KIP family of cyclin-dependent kinase inhibitors consisting of p21, p27, and p57. The different members of the CIP/KIP family share a conserved region at the N terminus that is required and sufficient for the inhibition of cyclin-Cdk complexes (6, 7). The p21 protein preferentially inactivates cyclin E/Cdk2 complexes, thereby blocking the inactivating phosphorylation of pRb, which represses genes important for S phase entry. In addition, p21 ...

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Protein Phosphatase 2A Activity Affects Histone H3 Phosphorylation and Transcription in Drosophila melanogaster

Cited by 98 publications

References 49 publications

MAP kinase-mediated phosphorylation of distinct pools of histone H3 at S10 or S28 via mitogen- and stress-activated kinase 1/2

MAP kinase-mediated phosphorylation of distinct pools of histone H3 at S10 or S28 via mitogen- and stress-activated kinase 1/2

Barrier-to-Autointegration Factor influences specific histone modifications

A Phosphorylation Switch Regulates the Transcriptional Activation of Cell Cycle Regulator p21 by Histone Deacetylase Inhibitors

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