The Experts below are selected from a list of 41742 Experts worldwide ranked by ideXlab platform

Jessica C Jimenez - One of the best experts on this subject based on the ideXlab platform.

  • interaction of fus and hdac1 regulates dna damage response and repair in neurons
    Nature Neuroscience, 2013
    Co-Authors: Wenyuan Wang, Susan C Su, Emma J Quinn, Megumi Sasaki, Jessica C Jimenez
    Abstract:

    Fused-in-Sarcoma (FUS) gene encodes an RNA/DNA binding protein whose mutations are linked to amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). This study shows that FUS functions in the neuronal DNA damage response by its recruitment to the site of DNA double-stranded breaks and by its interaction with Histone Deacetylase 1. The study also shows ALS/FTLD-associated mutant FUS is defective in DNA repair mechanism and that ALS/FTLD patients with FUS mutations have greater DNA damage.

  • interaction of fus and hdac1 regulates dna damage response and repair in neurons
    Nature Neuroscience, 2013
    Co-Authors: Wenyuan Wang, Susan C Su, Emma J Quinn, Megumi Sasaki, Jessica C Jimenez
    Abstract:

    Defects in DNA repair have been extensively linked to neurodegenerative diseases, but the exact mechanisms remain poorly understood. We found that FUS, an RNA/DNA-binding protein that has been linked to amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration, is important for the DNA damage response (DDR). The function of FUS in DDR involved a direct interaction with Histone Deacetylase 1 (HDAC1), and the recruitment of FUS to double-stranded break sites was important for proper DDR signaling. Notably, FUS proteins carrying familial ALS mutations were defective in DDR and DNA repair and showed a diminished interaction with HDAC1. Moreover, we observed increased DNA damage in human ALS patients harboring FUS mutations. Our findings suggest that an impaired DDR and DNA repair may contribute to the pathogenesis of neurodegenerative diseases linked to FUS mutations.

Joachim Alfer - One of the best experts on this subject based on the ideXlab platform.

  • Histone Deacetylase 1 and 3 protein expression in human breast cancer a tissue microarray analysis
    Breast Cancer Research and Treatment, 2005
    Co-Authors: Claudia A Krusche, P Wulfing, C Kersting, A Vloet, W Bocker, L Kiesel, Henning M Beier, Joachim Alfer
    Abstract:

    Impaired Histone acetylation was recognized to be involved in carcinogenesis. Furthermore, Histone Deacetylase (HDAC) inhibitors induce differentiation of breast cancer cells and inhibit tumour growth. These results prompted us to study HDAC-1 and -3 expression in breast tumours to establish their potential therapeutic and prognostic significance.

  • Histone Deacetylase 1 and 3 protein expression in human breast cancer a tissue microarray analysis
    Breast Cancer Research and Treatment, 2005
    Co-Authors: Claudia A Krusche, P Wulfing, C Kersting, A Vloet, W Bocker, L Kiesel, Henning M Beier, Joachim Alfer
    Abstract:

    Impaired Histone acetylation was recognized to be involved in carcinogenesis. Furthermore, Histone Deacetylase (HDAC) inhibitors induce differentiation of breast cancer cells and inhibit tumour growth. These results prompted us to study HDAC-1 and -3 expression in breast tumours to establish their potential therapeutic and prognostic significance. HDAC-1 und HDAC-3 protein expression was analyzed immunohistochemically on a tissue microarray (TMA) containing 600 core biopsies from 200 patients. HDAC-1 and -3 expression was correlated to steroid hormone receptor-, Her2/neu- and proliferation status of tumours as well as to overall and disease free survival. Moderate or strong nuclear immunoreactivity for HDAC-1 was observed in 39.8% and for HDAC-3 in 43.9% of breast carcinomas. HDAC-1 and -3 expression correlated significantly with oestrogen and progesterone receptor expression (both p< 0.001). HDAC-1 expression predicted significantly better disease free survival (DFS: p=0.044), in particular, in patients with small tumours of all differentiation types (DFS: p=0.016). Multivariate analysis demonstrated that HDAC-1 is an independent prognostic marker. Our data suggest that evaluation of HDAC-1 protein expression enables a more precise assessment of the prognosis of breast cancer patients. Thus, HDAC-1 expression analysis might be clinically useful to facilitate an individual, risk-directed, adjuvant systemic therapy in breast cancer patients.

Wenyuan Wang - One of the best experts on this subject based on the ideXlab platform.

  • interaction of fus and hdac1 regulates dna damage response and repair in neurons
    Nature Neuroscience, 2013
    Co-Authors: Wenyuan Wang, Susan C Su, Emma J Quinn, Megumi Sasaki, Jessica C Jimenez
    Abstract:

    Fused-in-Sarcoma (FUS) gene encodes an RNA/DNA binding protein whose mutations are linked to amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). This study shows that FUS functions in the neuronal DNA damage response by its recruitment to the site of DNA double-stranded breaks and by its interaction with Histone Deacetylase 1. The study also shows ALS/FTLD-associated mutant FUS is defective in DNA repair mechanism and that ALS/FTLD patients with FUS mutations have greater DNA damage.

  • interaction of fus and hdac1 regulates dna damage response and repair in neurons
    Nature Neuroscience, 2013
    Co-Authors: Wenyuan Wang, Susan C Su, Emma J Quinn, Megumi Sasaki, Jessica C Jimenez
    Abstract:

    Defects in DNA repair have been extensively linked to neurodegenerative diseases, but the exact mechanisms remain poorly understood. We found that FUS, an RNA/DNA-binding protein that has been linked to amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration, is important for the DNA damage response (DDR). The function of FUS in DDR involved a direct interaction with Histone Deacetylase 1 (HDAC1), and the recruitment of FUS to double-stranded break sites was important for proper DDR signaling. Notably, FUS proteins carrying familial ALS mutations were defective in DDR and DNA repair and showed a diminished interaction with HDAC1. Moreover, we observed increased DNA damage in human ALS patients harboring FUS mutations. Our findings suggest that an impaired DDR and DNA repair may contribute to the pathogenesis of neurodegenerative diseases linked to FUS mutations.

Christian Seiser - One of the best experts on this subject based on the ideXlab platform.

  • a monoclonal antibody specific for prophase phosphorylation of Histone Deacetylase 1 a readout for early mitotic cells
    mAbs, 2016
    Co-Authors: Chiara V Segre, Christian Seiser, Sara Loponte, Silvia Senese, Stefano Santaguida, Paolo Soffientini, Gabriela Grigorean, Mario Cinquanta, Giuseppe Ossolengo, Susanna Chiocca
    Abstract:

    Histone Deacetylases (HDACs) are modification enzymes that regulate a plethora of biological processes. HDAC1, a crucial epigenetic modifier, is deregulated in cancer and subjected to a variety of post-translational modifications. Here, we describe the generation of a new monoclonal antibody that specifically recognizes a novel highly dynamic prophase phosphorylation of serine 406-HDAC1, providing a powerful tool for detecting early mitotic cells.

  • protein kinase ck2 regulates the dimerization of Histone Deacetylase 1 hdac1 and hdac2 during mitosis
    Journal of Biological Chemistry, 2013
    Co-Authors: Dilshad H Khan, Shihua He, Christian Seiser, Stefan Winter, Jenny Yu, James R. Davie
    Abstract:

    Histone Deacetylase 1 (HDAC1) and HDAC2 are components of corepressor complexes that are involved in chromatin remodeling and regulation of gene expression by regulating dynamic protein acetylation. HDAC1 and -2 form homo- and heterodimers, and their activity is dependent upon dimer formation. Phosphorylation of HDAC1 and/or HDAC2 in interphase cells is required for the formation of HDAC corepressor complexes. In this study, we show that during mitosis, HDAC2 and, to a lesser extent, HDAC1 phosphorylation levels dramatically increase. When HDAC1 and -2 are displaced from the chromosome during metaphase, they dissociate from each other, but each enzyme remains in association with components of the HDAC corepressor complexes Sin3, NuRD, and CoREST as homodimers. Enzyme inhibition studies and mutational analyses demonstrated that protein kinase CK2-catalyzed phosphorylation of HDAC1 and -2 is crucial for the dissociation of these two enzymes. These results suggest that corepressor complexes, including HDAC1 or HDAC2 homodimers, might target different cellular proteins during mitosis.

  • Histone Deacetylase 1 and 2 controlled embryonic development and cell differentiation
    The International Journal of Developmental Biology, 2009
    Co-Authors: Reinhard Brunmeir, Sabine Lagger, Christian Seiser
    Abstract:

    During development from the fertilized egg to a multicellular organism, cell fate decisions have to be taken and cell lineage or tissue-specific gene expression patterns are created and maintained. These alterations in gene expression occur in the context of chromatin structure and are controlled by chromatin modifying enzymes. Gene disruption studies in different genetic systems have shown an essential role of various Histone Deacetylases (HDACs) during early development and cellular differentiation. In this review, we focus on the functions of the class I enzymes HDAC1 and HDAC2 during development in different organisms and summarise the current knowledge about their involvement in neurogenesis, myogenesis, haematopoiesis and epithelial cell differentiation.

  • role for Histone Deacetylase 1 in human tumor cell proliferation
    Molecular and Cellular Biology, 2007
    Co-Authors: Silvia Senese, Katrin Zaragoza, Simone Minardi, Ivan Muradore, Simona Ronzoni, Alfonso Passafaro, Loris Bernard, Giulio F Draetta, Myriam Alcalay, Christian Seiser
    Abstract:

    Posttranslational modifications of core Histones are central to the regulation of gene expression. Histone Deacetylases (HDACs) repress transcription by deacetylating Histones, and class I HDACs have a crucial role in mouse, Xenopus laevis, zebra fish, and Caenorhabditis elegans development. The role of individual class I HDACs in tumor cell proliferation was investigated using RNA interference-mediated protein knockdown. We show here that in the absence of HDAC1 cells can arrest either at the G1 phase of the cell cycle or at the G2/M transition, resulting in the loss of mitotic cells, cell growth inhibition, and an increase in the percentage of apoptotic cells. On the contrary, HDAC2 knockdown showed no effect on cell proliferation unless we concurrently knocked down HDAC1. Using gene expression profiling analysis, we found that inactivation of HDAC1 affected the transcription of specific target genes involved in proliferation and apoptosis. Furthermore, HDAC2 downregulation did not cause significant changes compared to control cells, while inactivation of HDAC1, HDAC1 plus HDAC2, or HDAC3 resulted in more distinct clusters. Loss of these HDACs might impair cell cycle progression by affecting not only the transcription of specific target genes but also other biological processes. Our data support the idea that a drug targeting specific HDACs could be highly beneficial in the treatment of cancer.

  • Histone Deacetylase 1 can repress transcription by binding to sp1
    Molecular and Cellular Biology, 1999
    Co-Authors: Angelika Doetzlhofer, Gerda Lagger, Hans Rotheneder, Manfred Koranda, Vladislav Kurtev, Gerald Brosch, Erhard Wintersberger, Christian Seiser
    Abstract:

    The members of the Sp1 transcription factor family can act as both negative and positive regulators of gene expression. Here we show that Sp1 can be a target for Histone Deacetylase 1 (HDAC1)-mediated transcriptional repression. The Histone Deacetylase inhibitor trichostatin A activates the chromosomally integrated murine thymidine kinase promoter in an Sp1-dependent manner. Coimmunoprecipitation experiments with Swiss 3T3 fibroblasts and 293 cells demonstrate that Sp1 and HDAC1 can be part of the same complex. The interaction between Sp1 and HDAC1 is direct and requires the carboxy-terminal domain of Sp1. Previously we have shown that the C terminus of Sp1 is necessary for the interaction with the transcription factor E2F1 (J. Karlseder, H. Rotheneder, and E. Wintersberger, Mol. Cell. Biol. 16:1659-1667, 1996). Coexpression of E2F1 interferes with HDAC1 binding to Sp1 and abolishes Sp1-mediated transcriptional repression. Our results indicate that one component of Sp1-dependent gene regulation involves competition between the transcriptional repressor HDAC1 and the transactivating factor E2F1.

Michael W. Van Dyke - One of the best experts on this subject based on the ideXlab platform.

  • parthenolide specifically depletes Histone Deacetylase 1 protein and induces cell death through ataxia telangiectasia mutated
    Chemistry & Biology, 2007
    Co-Authors: Y Vashisht N Gopal, Tarandeep S Arora, Michael W. Van Dyke
    Abstract:

    Summary Histone Deacetylases (HDACs), enzymes involved in chromatin remodeling, are promising targets for anticancer drug development. Several HDAC inhibitors (HDACi) are in clinical trials. One limitation of present HDACi is their nonspecificity, affecting many HDACs with similar effectiveness. We have identified a small molecule, the sesquiterpene lactone parthenolide (PN), which specifically depletes HDAC1 protein without affecting other class I/II HDACs. HDAC1 depletion occurred through proteasomal degradation and resulted in transcriptional consequences comparable to those observed with pan-HDACi. Surprisingly, HDAC1 depletion did not occur through the inflammation mediator IKK2, a known PN target and regulator of HDAC1. Rather, PN promoted HDAC1 depletion and cell death through the DNA-damage-transducer ataxia telangiectasia mutated. Our study suggests that modulating cellular HDAC protein levels with small molecules provides an alternative approach to specific HDAC inhibition and effective cancer treatment.

  • tumour necrosis factor α depletes Histone Deacetylase 1 protein through ikk2
    EMBO Reports, 2006
    Co-Authors: Y Vashisht N Gopal, Tarandeep S Arora, Michael W. Van Dyke
    Abstract:

    Class I Histone Deacetylases (HDACs) are ubiquitous enzymes that repress gene expression by deacetylating Histone tails and promoting chromatin compaction. Pro-inflammatory agents activate programmes of gene expression through transcription factors such as nuclear factor-κB (NF-κB), even in the context of ubiquitous HDAC activity. How this is accomplished remains unknown. We found that cells treated with the pro-inflammatory cytokine tumour necrosis factor-α rapidly and substantially reduced HDAC1 protein levels without affecting other class I HDACs. In addition, HDAC1 depletion occurred through protein degradation, required IKK2 activity and resulted in increased transcription from both NF-κB-associated and unassociated gene promoters. Our study suggests that the activation of programmes of gene expression by pro-inflammatory agents requires global changes in specific critical epigenetic regulators such as HDAC1.