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  1. Article ; Online: Histone acetyltransferase PCAF is required for Hedgehog-Gli-dependent transcription and cancer cell proliferation.

    Malatesta, Martina / Steinhauer, Cornelia / Mohammad, Faizaan / Pandey, Deo P / Squatrito, Massimo / Helin, Kristian

    Cancer research

    2013  Volume 73, Issue 20, Page(s) 6323–6333

    Abstract: The Hedgehog (Hh) signaling pathway plays an important role in embryonic patterning and development of many tissues and organs as well as in maintaining and repairing mature tissues in adults. Uncontrolled activation of the Hh-Gli pathway has been ... ...

    Abstract The Hedgehog (Hh) signaling pathway plays an important role in embryonic patterning and development of many tissues and organs as well as in maintaining and repairing mature tissues in adults. Uncontrolled activation of the Hh-Gli pathway has been implicated in developmental abnormalities as well as in several cancers, including brain tumors like medulloblastoma and glioblastoma. Inhibition of aberrant Hh-Gli signaling has, thus, emerged as an attractive approach for anticancer therapy; however, the mechanisms that mediate Hh-Gli signaling in vertebrates remain poorly understood. Here, we show that the histone acetyltransferase PCAF/KAT2B is an important factor of the Hh pathway. Specifically, we show that PCAF depletion impairs Hh activity and reduces expression of Hh target genes. Consequently, PCAF downregulation in medulloblastoma and glioblastoma cells leads to decreased proliferation and increased apoptosis. In addition, we found that PCAF interacts with GLI1, the downstream effector in the Hh-Gli pathway, and that PCAF or GLI1 loss reduces the levels of H3K9 acetylation on Hh target gene promoters. Finally, we observed that PCAF silencing reduces the tumor-forming potential of neural stem cells in vivo. In summary, our study identified the acetyltransferase PCAF as a positive cofactor of the Hh-Gli signaling pathway, leading us to propose PCAF as a candidate therapeutic target for the treatment of patients with medulloblastoma and glioblastoma.
    MeSH term(s) Animals ; Cell Growth Processes/physiology ; Cell Line, Tumor ; Glioblastoma/enzymology ; Glioblastoma/genetics ; Glioblastoma/metabolism ; Glioblastoma/pathology ; Hedgehog Proteins/biosynthesis ; Hedgehog Proteins/genetics ; Hedgehog Proteins/metabolism ; Humans ; Medulloblastoma/enzymology ; Medulloblastoma/genetics ; Medulloblastoma/metabolism ; Medulloblastoma/pathology ; Mice ; NIH 3T3 Cells ; Promoter Regions, Genetic ; RNA, Small Interfering ; Signal Transduction ; Transcription Factors/genetics ; Transcription Factors/metabolism ; Transcription, Genetic ; Transfection ; Zinc Finger Protein GLI1 ; p300-CBP Transcription Factors/genetics ; p300-CBP Transcription Factors/metabolism
    Chemical Substances GLI1 protein, human ; Hedgehog Proteins ; RNA, Small Interfering ; Transcription Factors ; Zinc Finger Protein GLI1 ; p300-CBP Transcription Factors (EC 2.3.1.48) ; p300-CBP-associated factor (EC 2.3.1.48)
    Language English
    Publishing date 2013-10-15
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1432-1
    ISSN 1538-7445 ; 0008-5472
    ISSN (online) 1538-7445
    ISSN 0008-5472
    DOI 10.1158/0008-5472.CAN-12-4660
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Detection of changes in gene regulatory patterns, elicited by perturbations of the Hsp90 molecular chaperone complex, by visualizing multiple experiments with an animation

    Echeverría Pablo C / Forafonov Fedor / Pandey Deo P / Mühlebach Guillaume / Picard Didier

    BioData Mining, Vol 4, Iss 1, p

    2011  Volume 15

    Abstract: Abstract Background To make sense out of gene expression profiles, such analyses must be pushed beyond the mere listing of affected genes. For example, if a group of genes persistently display similar changes in expression levels under particular ... ...

    Abstract Abstract Background To make sense out of gene expression profiles, such analyses must be pushed beyond the mere listing of affected genes. For example, if a group of genes persistently display similar changes in expression levels under particular experimental conditions, and the proteins encoded by these genes interact and function in the same cellular compartments, this could be taken as very strong indicators for co-regulated protein complexes. One of the key requirements is having appropriate tools to detect such regulatory patterns. Results We have analyzed the global adaptations in gene expression patterns in the budding yeast when the Hsp90 molecular chaperone complex is perturbed either pharmacologically or genetically. We integrated these results with publicly accessible expression, protein-protein interaction and intracellular localization data. But most importantly, all experimental conditions were simultaneously and dynamically visualized with an animation. This critically facilitated the detection of patterns of gene expression changes that suggested underlying regulatory networks that a standard analysis by pairwise comparison and clustering could not have revealed. Conclusions The results of the animation-assisted detection of changes in gene regulatory patterns make predictions about the potential roles of Hsp90 and its co-chaperone p23 in regulating whole sets of genes. The simultaneous dynamic visualization of microarray experiments, represented in networks built by integrating one's own experimental with publicly accessible data, represents a powerful discovery tool that allows the generation of new interpretations and hypotheses.
    Keywords gene expression ; microarray analysis ; visualization ; yeast ; stress response ; molecular chaperones ; Hsp90 ; inhibitor ; gene deletion ; Computer applications to medicine. Medical informatics ; R858-859.7 ; Analysis ; QA299.6-433
    Subject code 570 ; 612
    Language English
    Publishing date 2011-06-01T00:00:00Z
    Publisher BMC
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Detection of changes in gene regulatory patterns, elicited by perturbations of the Hsp90 molecular chaperone complex, by visualizing multiple experiments with an animation.

    Echeverría, Pablo C / Forafonov, Fedor / Pandey, Deo P / Mühlebach, Guillaume / Picard, Didier

    BioData mining

    2011  Volume 4, Issue 1, Page(s) 15

    Abstract: Background: To make sense out of gene expression profiles, such analyses must be pushed beyond the mere listing of affected genes. For example, if a group of genes persistently display similar changes in expression levels under particular experimental ... ...

    Abstract Background: To make sense out of gene expression profiles, such analyses must be pushed beyond the mere listing of affected genes. For example, if a group of genes persistently display similar changes in expression levels under particular experimental conditions, and the proteins encoded by these genes interact and function in the same cellular compartments, this could be taken as very strong indicators for co-regulated protein complexes. One of the key requirements is having appropriate tools to detect such regulatory patterns.
    Results: We have analyzed the global adaptations in gene expression patterns in the budding yeast when the Hsp90 molecular chaperone complex is perturbed either pharmacologically or genetically. We integrated these results with publicly accessible expression, protein-protein interaction and intracellular localization data. But most importantly, all experimental conditions were simultaneously and dynamically visualized with an animation. This critically facilitated the detection of patterns of gene expression changes that suggested underlying regulatory networks that a standard analysis by pairwise comparison and clustering could not have revealed.
    Conclusions: The results of the animation-assisted detection of changes in gene regulatory patterns make predictions about the potential roles of Hsp90 and its co-chaperone p23 in regulating whole sets of genes. The simultaneous dynamic visualization of microarray experiments, represented in networks built by integrating one's own experimental with publicly accessible data, represents a powerful discovery tool that allows the generation of new interpretations and hypotheses.
    Language English
    Publishing date 2011-06-14
    Publishing country England
    Document type Journal Article
    ZDB-ID 2438773-3
    ISSN 1756-0381 ; 1756-0381
    ISSN (online) 1756-0381
    ISSN 1756-0381
    DOI 10.1186/1756-0381-4-15
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: HicA of Escherichia coli defines a novel family of translation-independent mRNA interferases in bacteria and archaea.

    Jørgensen, Mikkel G / Pandey, Deo P / Jaskolska, Milena / Gerdes, Kenn

    Journal of bacteriology

    2008  Volume 191, Issue 4, Page(s) 1191–1199

    Abstract: Toxin-antitoxin (TA) loci are common in free-living bacteria and archaea. TA loci encode a stable toxin that is neutralized by a metabolically unstable antitoxin. The antitoxin can be either a protein or an antisense RNA. So far, six different TA gene ... ...

    Abstract Toxin-antitoxin (TA) loci are common in free-living bacteria and archaea. TA loci encode a stable toxin that is neutralized by a metabolically unstable antitoxin. The antitoxin can be either a protein or an antisense RNA. So far, six different TA gene families, in which the antitoxins are proteins, have been identified. Recently, Makarova et al. (K. S. Makarova, N. V. Grishin, and E. V. Koonin, Bioinformatics 22:2581-2584, 2006) suggested that the hicAB loci constitute a novel TA gene family. Using the hicAB locus of Escherichia coli K-12 as a model system, we present evidence that supports this inference: expression of the small HicA protein (58 amino acids [aa]) induced cleavage in three model mRNAs and tmRNA. Concomitantly, the global rate of translation was severely reduced. Using tmRNA as a substrate, we show that HicA-induced cleavage does not require the target RNA to be translated. Expression of HicB (145 aa) prevented HicA-mediated inhibition of cell growth. These results suggest that HicB neutralizes HicA and therefore functions as an antitoxin. As with other antitoxins (RelB and MazF), HicB could resuscitate cells inhibited by HicA, indicating that ectopic production of HicA induces a bacteriostatic rather than a bactericidal condition. Nutrient starvation induced strong hicAB transcription that depended on Lon protease. Mining of 218 prokaryotic genomes revealed that hicAB loci are abundant in bacteria and archaea.
    MeSH term(s) Archaea/enzymology ; Escherichia coli/genetics ; Escherichia coli/metabolism ; Escherichia coli Proteins/genetics ; Escherichia coli Proteins/metabolism ; Gene Expression Regulation, Bacterial/physiology ; Multigene Family ; Protein Biosynthesis ; RNA, Messenger/metabolism
    Chemical Substances Escherichia coli Proteins ; RNA, Messenger
    Language English
    Publishing date 2008-12-05
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2968-3
    ISSN 1098-5530 ; 0021-9193
    ISSN (online) 1098-5530
    ISSN 0021-9193
    DOI 10.1128/JB.01013-08
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: EZH2 is a potential therapeutic target for H3K27M-mutant pediatric gliomas.

    Mohammad, Faizaan / Weissmann, Simon / Leblanc, Benjamin / Pandey, Deo P / Højfeldt, Jonas W / Comet, Itys / Zheng, Chunqin / Johansen, Jens Vilstrup / Rapin, Nicolas / Porse, Bo T / Tvardovskiy, Andrey / Jensen, Ole N / Olaciregui, Nagore G / Lavarino, Cinzia / Suñol, Mariona / de Torres, Carmen / Mora, Jaume / Carcaboso, Angel M / Helin, Kristian

    Nature medicine

    2017  Volume 23, Issue 4, Page(s) 483–492

    Abstract: Diffuse intrinsic pontine glioma (DIPG) is an aggressive brain tumor that is located in the pons and primarily affects children. Nearly 80% of DIPGs harbor mutations in histone H3 genes, wherein lysine 27 is substituted with methionine (H3K27M). H3K27M ... ...

    Abstract Diffuse intrinsic pontine glioma (DIPG) is an aggressive brain tumor that is located in the pons and primarily affects children. Nearly 80% of DIPGs harbor mutations in histone H3 genes, wherein lysine 27 is substituted with methionine (H3K27M). H3K27M has been shown to inhibit polycomb repressive complex 2 (PRC2), a multiprotein complex responsible for the methylation of H3 at lysine 27 (H3K27me), by binding to its catalytic subunit EZH2. Although DIPGs with the H3K27M mutation show global loss of H3K27me3, several genes retain H3K27me3. Here we describe a mouse model of DIPG in which H3K27M potentiates tumorigenesis. Using this model and primary patient-derived DIPG cell lines, we show that H3K27M-expressing tumors require PRC2 for proliferation. Furthermore, we demonstrate that small-molecule EZH2 inhibitors abolish tumor cell growth through a mechanism that is dependent on the induction of the tumor-suppressor protein p16
    MeSH term(s) Animals ; Benzamides/pharmacology ; Brain Neoplasms/genetics ; Brain Stem Neoplasms/genetics ; CRISPR-Cas Systems ; Cell Line, Tumor ; Cell Proliferation/genetics ; Chromatin Immunoprecipitation ; Chromatography, Liquid ; Cyclin-Dependent Kinase Inhibitor p16/drug effects ; Cyclin-Dependent Kinase Inhibitor p16/genetics ; Disease Models, Animal ; Enhancer of Zeste Homolog 2 Protein/antagonists & inhibitors ; Enhancer of Zeste Homolog 2 Protein/genetics ; Gene Knockout Techniques ; Glioblastoma/genetics ; Glioma/genetics ; Histones/genetics ; Humans ; Immunohistochemistry ; In Situ Hybridization, Fluorescence ; Indazoles/pharmacology ; Mice ; Mice, SCID ; Molecular Targeted Therapy ; Mutation ; Neoplasm Transplantation ; Neural Stem Cells ; Polycomb Repressive Complex 2/genetics ; Pyridones/pharmacology ; Tandem Mass Spectrometry ; Tumor Suppressor Protein p14ARF/drug effects ; Tumor Suppressor Protein p14ARF/genetics
    Chemical Substances Benzamides ; Cyclin-Dependent Kinase Inhibitor p16 ; GSK343 ; Histones ; Indazoles ; Pyridones ; Tumor Suppressor Protein p14ARF ; EZH2 protein, human (EC 2.1.1.43) ; Enhancer of Zeste Homolog 2 Protein (EC 2.1.1.43) ; Ezh2 protein, mouse (EC 2.1.1.43) ; Polycomb Repressive Complex 2 (EC 2.1.1.43) ; tazemetostat (Q40W93WPE1)
    Language English
    Publishing date 2017-02-27
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1220066-9
    ISSN 1546-170X ; 1078-8956
    ISSN (online) 1546-170X
    ISSN 1078-8956
    DOI 10.1038/nm.4293
    Database MEDical Literature Analysis and Retrieval System OnLINE

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