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Yasunori Sugiyama, Sho Yamashita, Yuuki Uezato, Yukako Senga, Syouichi Katayama, Naoki Goshima, Yasushi Shigeri, Noriyuki Sueyoshi, Isamu Kameshita
To analyze a variety of protein phosphatases, we developed phosphorylated TandeMBP (P-TandeMBP), in which two different mouse myelin basic protein isoforms were fused in tandem, as a protein phosphatase substrate. P-TandeMBP was prepared efficiently in four steps: (1) phosphorylation of TandeMBP by a protein kinase mixture (Ca(2+)/calmodulin-dependent protein kinase Iδ, casein kinase 1δ, and extracellular signal-regulated kinase 2); (2) precipitation of both P-TandeMBP and protein kinases to remove ATP, Pi, and ADP; (3) acid extraction of P-TandeMBP with HCl to remove protein kinases; and (4) neutralization of the solution that contains P-TandeMBP with Tris...
November 15, 2016: Analytical Biochemistry
Swapna Aravind Gudipaty, Iván D'Orso
Transcription elongation is a critical regulatory step in the gene expression cycle. One key regulator of the switch between transcription initiation and elongation is the P-TEFb kinase, which phosphorylates RNA polymerase II (Pol II) and several negative elongation factors to relieve the elongation block at paused promoters to facilitate productive elongation. Here, we highlight recent findings signifying the role of the PPM1G/PP2Cγ phosphatase in activating and maintaining the active transcription elongation state by regulating the availability of P-TEFb and blocking its assembly into the catalytic inactive 7SK small nuclear ribonucleoprotein (snRNP) complex...
2016: RNA & Disease
K Xu, L Wang, W Feng, Y Feng, H-Kg Shu
Id1 is a helix-loop-helix transcriptional modulator that increases the aggressiveness of malignant glial neoplasms. Since most glioblastomas (GBMs) show increased phosphatidylinositol-3 kinase (PI-3K) signaling, we sought to determine whether this pathway regulates Id1 expression. Higher basal Id1 expression correlates with dysregulated PI-3K signaling in multiple established GBM cell lines. Further characterization of PI-3K-dependent Id1 regulation reveals that chemical or genetic inhibition of PI-3K signaling reduces Id1 protein but not mRNA expression...
April 11, 2016: Oncogene
Swapna Aravind Gudipaty, Ryan P McNamara, Emily L Morton, Iván D'Orso
Transcription elongation programs are vital for the precise regulation of several biological processes. One key regulator of such programs is the P-TEFb kinase, which phosphorylates RNA polymerase II (Pol II) once released from the inhibitory 7SK small nuclear ribonucleoprotein (snRNP) complex. Although mechanisms of P-TEFb release from the snRNP are becoming clearer, how P-TEFb remains in the 7SK-unbound state to sustain transcription elongation programs remains unknown. Here we report that the PPM1G phosphatase (inducibly recruited by nuclear factor κB [NF-κB] to target promoters) directly binds 7SK RNA and the kinase inhibitor Hexim1 once P-TEFb has been released from the 7SK snRNP...
November 2015: Molecular and Cellular Biology
Barbara Ruggeri, Charlotte Nymberg, Eero Vuoksimaa, Anbarasu Lourdusamy, Cybele P Wong, Fabiana M Carvalho, Tianye Jia, Anna Cattrell, Christine Macare, Tobias Banaschewski, Gareth J Barker, Arun L W Bokde, Uli Bromberg, Christian Büchel, Patricia J Conrod, Mira Fauth-Bühler, Herta Flor, Vincent Frouin, Jürgen Gallinat, Hugh Garavan, Penny Gowland, Andreas Heinz, Bernd Ittermann, Jean-Luc Martinot, Frauke Nees, Zdenka Pausova, Tomáš Paus, Marcella Rietschel, Trevor Robbins, Michael N Smolka, Rainer Spanagel, Georgy Bakalkin, Jonathan Mill, Wolfgang H Sommer, Richard J Rose, Jia Yan, Fazil Aliev, Danielle Dick, Jaakko Kaprio, Sylvane Desrivières, Gunter Schumann
OBJECTIVE: The genetic component of alcohol use disorder is substantial, but monozygotic twin discordance indicates a role for nonheritable differences that could be mediated by epigenetics. Despite growing evidence associating epigenetics and psychiatric disorders, it is unclear how epigenetics, particularly DNA methylation, relate to brain function and behavior, including drinking behavior. METHOD: The authors carried out a genome-wide analysis of DNA methylation of 18 monozygotic twin pairs discordant for alcohol use disorder and validated differentially methylated regions...
June 2015: American Journal of Psychiatry
Paul A Renauer, Guher Saruhan-Direskeneli, Patrick Coit, Adam Adler, Kenan Aksu, Gokhan Keser, Fatma Alibaz-Oner, Sibel Z Aydin, Sevil Kamali, Murat Inanc, Simon Carette, David Cuthbertson, Gary S Hoffman, Servet Akar, Fatos Onen, Nurullah Akkoc, Nader A Khalidi, Curry Koening, Omer Karadag, Sedat Kiraz, Carol A Langford, Kathleen Maksimowicz-McKinnon, Carol A McAlear, Zeynep Ozbalkan, Askin Ates, Yasar Karaaslan, Nursen Duzgun, Paul A Monach, Huseyin T E Ozer, Eren Erken, Mehmet A Ozturk, Ayten Yazici, Ayse Cefle, Ahmet Mesut Onat, Bunyamin Kisacik, Christian Pagnoux, Timucin Kasifoglu, Emire Seyahi, Izzet Fresko, Philip Seo, Antoine G Sreih, Kenneth J Warrington, Steven R Ytterberg, Veli Cobankara, Deborah S Cunninghame-Graham, Timothy J Vyse, Omer N Pamuk, S Ercan Tunc, Ediz Dalkilic, Muge Bicakcigil, Sibel P Yentur, Jonathan D Wren, Peter A Merkel, Haner Direskeneli, Amr H Sawalha
OBJECTIVE: Takayasu arteritis is a rare large vessel vasculitis with incompletely understood etiology. This study was undertaken to perform the first unbiased genome-wide association analysis of Takayasu arteritis. METHODS: Two independent cohorts of patients with Takayasu arteritis from Turkey and North America were included in our study. The Turkish cohort consisted of 559 patients and 489 controls, and the North American cohort consisted of 134 patients and 1,047 controls of European ancestry...
May 2015: Arthritis & Rheumatology
Alma Husedzinovic, Beate Neumann, Jürgen Reymann, Stefanie Draeger-Meurer, Ashwin Chari, Holger Erfle, Utz Fischer, Oliver J Gruss
The survival motor neuron (SMN) complex fulfils essential functions in the assembly of snRNPs, which are key components in the splicing of pre-mRNAs. Little is known about the regulation of SMN complex activity by posttranslational modification despite its complicated phosphorylation pattern. Several phosphatases had been implicated in the regulation of SMN, including the nuclear phosphatases PPM1G and PP1γ. Here we systematically screened all human phosphatase gene products for a regulatory role in the SMN complex...
January 15, 2015: Molecular Biology of the Cell
Neelam Chaudhary, Subbareddy Maddika
The balance between transcription factor p73 and its functionally opposing N-terminally truncated ΔNp73 isoform is critical for cell survival, but the precise mechanism that regulates their levels is not clear. In our study, we identified WWP2, an E3 ligase, as a novel p73-associated protein that ubiquitinates and degrades p73. In contrast, WWP2 heterodimerizes with another E3 ligase, WWP1, which specifically ubiquitinates and degrades ΔNp73. Further, we identified phosphatase PPM1G as a functional switch that controls the balance between monomeric WWP2 and a WWP2/WWP1 heterodimeric state in the cell...
October 1, 2014: Molecular and Cellular Biology
Ryan P McNamara, Jennifer L McCann, Swapna Aravind Gudipaty, Iván D'Orso
The transition from transcription initiation into elongation is controlled by transcription factors, which recruit positive transcription elongation factor b (P-TEFb) to promoters to phosphorylate RNA polymerase II. A fraction of P-TEFb is recruited as part of the inhibitory 7SK small nuclear ribonucleoprotein particle (snRNP), which inactivates the kinase and prevents elongation. However, it is unclear how P-TEFb is captured from the promoter-bound 7SK snRNP to activate elongation. Here, we describe a mechanism by which transcription factors mediate the enzymatic release of P-TEFb from the 7SK snRNP at promoters to trigger activation in a gene-specific manner...
December 12, 2013: Cell Reports
Chang Pan, Hong-Da Liu, Zheng Gong, Xiao Yu, Xu-Ben Hou, Di-Dong Xie, Xi-Bin Zhu, Hao-Wen Li, Jun-Yi Tang, Yun-Fei Xu, Jia-Qi Yu, Lian-Ying Zhang, Hao Fang, Kun-Hong Xiao, Yu-Guo Chen, Jiang-Yun Wang, Qi Pang, Wei Chen, Jin-Peng Sun
The heavy metal cadmium is a non-degradable pollutant. By screening the effects of a panel of metal ions on the phosphatase activity, we unexpectedly identified cadmium as a potent inhibitor of PPM1A and PPM1G. In contrast, low micromolar concentrations of cadmium did not inhibit PP1 or tyrosine phosphatases. Kinetic studies revealed that cadmium inhibits PPM phosphatases through the M1 metal ion binding site. In particular, the negative charged D441 in PPM1G specific recognized cadmium. Our results suggest that cadmium is likely a potent inhibitor of most PPM family members except for PHLPPs...
2013: Scientific Reports
Jianyu Liu, Payton D Stevens, Nichole E Eshleman, Tianyan Gao
Protein translation initiation is a tightly controlled process responding to nutrient availability and mitogen stimulation. Serving as one of the most important negative regulators of protein translation, 4E binding protein 1 (4E-BP1) binds to translation initiation factor 4E and inhibits cap-dependent translation in a phosphorylation-dependent manner. Although it has been demonstrated previously that the phosphorylation of 4E-BP1 is controlled by mammalian target of rapamycin in the mammalian target of rapamycin complex 1, the mechanism underlying the dephosphorylation of 4E-BP1 remains elusive...
August 9, 2013: Journal of Biological Chemistry
William H Foster, Adam Langenbacher, Chen Gao, Jaunian Chen, Yibin Wang
BACKGROUND: PPM1G is a nuclear localized serine/threonine phosphatase implicated to be a regulator of chromatin remodeling, mRNA splicing, and DNA damage. However, its in vivo function is unknown. RESULTS: Here we show that ppm1g expression is highly enriched in the central nervous system during mouse and zebrafish development. ppm1g(-/-) mice were embryonic lethal with incomplete penetrance after E12.5. Rostral defects, including neural tube and craniofacial defects were observed in ppm1g(-/-) embryos associated with increased cell death in the neural epithelium...
September 2013: Developmental Dynamics: An Official Publication of the American Association of Anatomists
David M Perry, Kazuyuki Kitatani, Patrick Roddy, Mohamad El-Osta, Yusuf A Hannun
Ceramide is a bioactive sphingolipid with many associated biological outcomes, yet there is a significant gap in our current understanding of how ceramide mediates these processes. Previously, ceramide has been shown to activate protein phosphatase (PP) 1 and 2A. While continuing this line of work, a late fraction from a Mono-Q column was consistently observed to be activated by ceramide, yet PP1 and PP2A were undetectable in this fraction. Proteomic analysis of this fraction revealed the identity of the phosphatase to be PP2Cγ/PPM1G...
August 2012: Journal of Lipid Research
Petra Beli, Natalia Lukashchuk, Sebastian A Wagner, Brian T Weinert, Jesper V Olsen, Linda Baskcomb, Matthias Mann, Stephen P Jackson, Chunaram Choudhary
The regulatory networks of the DNA damage response (DDR) encompass many proteins and posttranslational modifications. Here, we use mass spectrometry-based proteomics to analyze the systems-wide response to DNA damage by parallel quantification of the DDR-regulated phosphoproteome, acetylome, and proteome. We show that phosphorylation-dependent signaling networks are regulated more strongly compared to acetylation. Among the phosphorylated proteins identified are many putative substrates of DNA-PK, ATM, and ATR kinases, but a majority of phosphorylated proteins do not share the ATM/ATR/DNA-PK target consensus motif, suggesting an important role of downstream kinases in amplifying DDR signals...
April 27, 2012: Molecular Cell
Svetlana V Khoronenkova, Irina I Dianova, Nicola Ternette, Benedikt M Kessler, Jason L Parsons, Grigory L Dianov
The deubiquitylation enzyme USP7/HAUSP plays a major role in regulating genome stability and cancer prevention by controlling the key proteins involved in the DNA damage response. Despite this important role in controlling other proteins, USP7 itself has not been recognized as a target for regulation. Here, we report that USP7 regulation plays a central role in DNA damage signal transmission. We find that stabilization of Mdm2, and correspondingly p53 downregulation in unstressed cells, is accomplished by a specific isoform of USP7 (USP7S), which is phosphorylated at serine 18 by the protein kinase CK2...
March 30, 2012: Molecular Cell
Scoty M Hearst, Andrew S Gilder, Sandeep S Negi, Misty D Davis, Eric M George, Angela A Whittom, Cory G Toyota, Alma Husedzinovic, Oliver J Gruss, Michael D Hebert
Cajal bodies (CBs) are nuclear structures that are thought to have diverse functions, including small nuclear ribonucleoprotein (snRNP) biogenesis. The phosphorylation status of coilin, the CB marker protein, might impact CB formation. We hypothesize that primary cells, which lack CBs, contain different phosphoisoforms of coilin compared with that found in transformed cells, which have CBs. Localization, self-association and fluorescence recovery after photobleaching (FRAP) studies on coilin phosphomutants all suggest this modification impacts the function of coilin and may thus contribute towards CB formation...
June 1, 2009: Journal of Cell Science
Sebastian Petri, Matthias Grimmler, Sabine Over, Utz Fischer, Oliver J Gruss
The survival motor neuron (SMN) complex functions in maturation of uridine-rich small nuclear ribonucleoprotein (RNP) particles. SMN mediates the cytoplasmic assembly of Sm proteins onto uridine-rich small RNAs, and then participates in targeting RNPs to nuclear Cajal bodies (CBs). Recent studies have suggested that phosphorylation might control localization and function of the SMN complex. Here, we show that the nuclear phosphatase PPM1G/PP2Cgamma interacts with and dephosphorylates the SMN complex. Small interfering RNA knockdown of PPM1G leads to an altered phosphorylation pattern of SMN and Gemin3, loss of SMN from CBs, and reduced stability of SMN...
November 5, 2007: Journal of Cell Biology
Hiroshi Kimura, Nanako Takizawa, Eric Allemand, Tetsuya Hori, Francisco J Iborra, Naohito Nozaki, Michiko Muraki, Masatoshi Hagiwara, Adrian R Krainer, Tatsuo Fukagawa, Katsuya Okawa
In eukaryotic nuclei, DNA is wrapped around a protein octamer composed of the core histones H2A, H2B, H3, and H4, forming nucleosomes as the fundamental units of chromatin. The modification and deposition of specific histone variants play key roles in chromatin function. In this study, we established an in vitro system based on permeabilized cells that allows the assembly and exchange of histones in situ. H2A and H2B, each tagged with green fluorescent protein (GFP), are incorporated into euchromatin by exchange independently of DNA replication, and H3...
November 6, 2006: Journal of Cell Biology
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