scholarly journals Protein Kinase D2 Controls Cardiac Valve Formation in Zebrafish by Regulating Histone Deacetylase 5 Activity

Circulation ◽  
2011 ◽  
Vol 124 (3) ◽  
pp. 324-334 ◽  
Author(s):  
Steffen Just ◽  
Ina M. Berger ◽  
Benjamin Meder ◽  
Johannes Backs ◽  
Andreas Keller ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Histone Deacetylase ◽  
Cardiac Valve ◽  
Valve Formation

Abstract 3407: The Transcriptional Mediator Complex Is Essential For Cardiac Valve Formation

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Steffen Just ◽  
Ina Berger ◽  
Benjamin Meder ◽  
David Hassel ◽  
Alexander Hess ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Model Organism ◽  
Mutant Phenotype ◽  
Cardiac Valve ◽  
Mediator Complex ◽  
Zebrafish Embryos ◽  
Sequence Alignments ◽  
Human Cardiomyocytes ◽  
Ping Pong ◽  
Valve Formation

The genetic causes of congenital heart diseases especially cardiac valve disorders are mostly unknown. During the last decade, the zebrafish became an excellent and established model organism (1) to uncover these genetic defects and (2) to elucidate the underlying molecular pathomechanisms. We recently isolated the zebrafish mutation ping pong ( png m683 ) in a large-scale ENU-mutagenesis screen for recessive lethal mutations that perturb cardiac function. png mutant zebrafish embryos show pathologically developed cardiac valves. Due to malformation of the cardiac AV valves, png mutant zebrafish embryos exhibit vigorous regurgitation of blood between the atrium and the ventricle. Furthermore, as a result of the cardiac valve malformation and cardiac dysfunction png mutants die at day 6 post fertilization. Expression of several factors known to be crucial for the proper development and formation of the atrio-ventricluar canal (e.g. notch1b, bmp4 or versican) is significantly altered in png mutant zebrafish hearts. By a positional cloning approach we demonstrate that the ping pong phenotype is caused by a promotor mutation in a zebrafish gene encoding for a novel component of the “transcriptional mediator complex”. This mediator complex is a multi-protein complex that acts as a transcriptional coactivator and transduces informations from transcription factors to the RNA polymerase II. png is strongly expressed in zebrafish as well as human cardiomyocytes. Furthermore, sequence alignments demonstrate the evolutionary conservation of the ping pong gene product. Gene specific knock-down studies by means of modified antisense oligonucleotides reveal a phenocopy of the png mutant phenotype whereas injection of the gene-specific mRNA in png mutant embryos restores the mutant phenotype indicating that png is indeed responsible for the observed phenotype. The zebrafish evolved as an excellent model organism to study the molecular signalling pathways involved in cardiac valve formation. By detailed characterization of the zebrafish line ping pong we will obtain new insights into these molecular mechanisms especially the transcriptional control of valve formation and therefore the pathomechanisms of human cardiac valve disorders.

scholarly journals Identification of Combinations of Protein Kinase C Activators and Histone Deacetylase Inhibitors that Potently Reactivate Latent HIV

Viruses ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 609
Author(s):  
Francesca Curreli ◽  
Shahad Ahmed ◽  
Sofia M. Benedict Victor ◽  
Asim K. Debnath
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Synergistic Effect ◽  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Latent Virus ◽  
Hiv Latency ◽  
Kinase C ◽  
Protein Kinase C Activators ◽  
Latent Hiv

Combination antiretroviral therapy (cART) is successful in maintaining undetectable levels of HIV in the blood; however, the persistence of latent HIV reservoirs has become the major barrier for a HIV cure. Substantial efforts are underway in finding the best latency-reversing agents (LRAs) to purge the latent viruses from the reservoirs. We hypothesize that identifying the right combination of LRAs will be the key to accomplishing that goal. In this study, we evaluated the effect of combinations of three protein kinase C activators (prostratin, (-)-indolactam V, and TPPB) with four histone deacetylase inhibitors (AR-42, PCI-24781, givinostat, and belinostat) on reversing HIV latency in different cell lines including in a primary CD4+ T-cell model. Combinations including indolactam and TPPB with AR-42 and PCI produced a strong synergistic effect in reactivating latent virus as indicated by higher p24 production and envelope gp120 expression. Furthermore, treatment with TPPB and indolactam greatly downregulated the cellular receptor CD4. Indolactam/AR-42 combination emerged from this study as the best combination that showed a strong synergistic effect in reactivating latent virus. Although AR-42 alone did not downregulate CD4 expression, indolactam/AR-42 showed the most efficient downregulation. Our results suggest that indolactam/AR-42 is the most effective combination, showing a strong synergistic effect in reversing HIV latency combined with the most efficient CD4 downregulation.

The transcription factor NF-ATc is essential for cardiac valve formation

Nature ◽  
10.1038/32426 ◽  
1998 ◽  
Vol 392 (6672) ◽  
pp. 186-190 ◽  
Author(s):  
Ann M. Ranger ◽  
Michael J. Grusby ◽  
Martin R. Hodge ◽  
Ellen M. Gravallese ◽  
Fabienne Charles de la Brousse ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cardiac Valve ◽  
Valve Formation

scholarly journals Homeodomain-Interacting Protein Kinase 1 Modulates Daxx Localization, Phosphorylation, and Transcriptional Activity

2003 ◽  
Vol 23 (3) ◽  
pp. 950-960 ◽  
Author(s):  
Jeffrey A. Ecsedy ◽  
Jennifer S. Michaelson ◽  
Philip Leder
Keyword(s):  
Protein Kinase ◽  
Histone Deacetylase ◽  
Transcriptional Repression ◽  
Transcriptional Activity ◽  
Transcriptional Repressor ◽  
Transcriptional Regulators ◽  
Kinase Domain ◽  
Promyelocytic Leukemia ◽  
Interacting Protein ◽  
Promyelocytic Leukemia Protein

ABSTRACT We describe an interaction between homeodomain-interacting protein kinase 1 (HIPK1) and Daxx, two transcriptional regulators important in transducing growth-regulatory signals. We demonstrate that HIPK1 is ubiquitously expressed in mice and humans and localizes predominantly to the nucleus. Daxx normally resides within the nucleus in promyelocytic leukemia protein (PML) oncogenic domains (PODs), where it physically interacts with PML. Under certain circumstances, Daxx is relocalized from PODs to chromatin, where it then acts as a transcriptional repressor through an association with histone deacetylase (HDAC1). We propose two novel mechanisms for regulating the activity of Daxx, both mediated by HIPK1. First, HIPK1 physically interacts with Daxx in cells and consequently relocalizes Daxx from PODs. Daxx relocalization disrupts its interaction with PML and augments its interaction with HDAC1, likely influencing Daxx activity. Although the relocalization of Daxx from PODs is phosphorylation independent, an active HIPK1 kinase domain is required, suggesting that HIPK1 autophosphorylation is important in this interaction. Second, HIPK1 phosphorylates Daxx on Ser 669, and phosphorylation of this site is important in modulating the ability of Daxx to function as a transcriptional repressor. Mutation of Daxx Ser 669 to Ala results in increased repression in three of four transcriptional reporters, suggesting that phosphorylation by HIPK1 diminishes Daxx transcriptional repression of specific promoters. Taken together, our results indicate that HIPK1 and Daxx collaborate in regulating transcription.

scholarly journals Thymosin Beta4 Regulates Cardiac Valve Formation Via Endothelial-Mesenchymal Transformation in Zebrafish Embryos

2014 ◽  
Vol 37 (4) ◽  
pp. 330-336 ◽  
Author(s):  
Sun-Hye Shin ◽  
Sangkyu Lee ◽  
Jong-Sup Bae ◽  
Jun-Goo Jee ◽  
Hee-Jae Cha ◽  
...  
Keyword(s):  
Cardiac Valve ◽  
Zebrafish Embryos ◽  
Mesenchymal Transformation ◽  
Valve Formation ◽  
Thymosin Beta4
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