1,720,981 research outputs found
RBM20 deficiency prevents expression of the mature N2B isoform of titin in cardiomyocytes derived from human induced pluripotent stem cells
No full textRBM20 deficiency prevents expression of the mature N2B isoform of titin in cardiomyocytes derived from human induced pluripotent stem cells
No full textA Feedback Circuit between Transcriptional Activation and Self-Destruction of Gcn4 Separates Its Metabolic and Morphogenic Response in Diploid Yeasts
No full textThe basic zipper Gcn4 protein activates transcription in the yeast Saccharomyces cerevisiae in response to amino acid starvation. This includes numerous metabolic genes of amino acid or purine biosynthesis and the developmental cell-surface flocculin gene FLO11, which is required for diploid pseudohyphae formation and for adhesion upon nutrient starvation. We separated the metabolic from the developmental response by screening for GCN4 alleles that allow growth during amino acid starvation but are impaired in adhesion and are unable to form pseudohyphae. The identified Gcn4(L267S) variant carries an amino acid substitution in the third of the four conserved leucines of the zipper dimerization domain. This mutation abolished FLO11 expression and results in reduced but sufficient transcriptional activity for amino acid biosynthetic genes. The Leu267Ser substitution impairs Gcn4 homodimer formation and is a significantly more stable protein than the wild-type protein. A helix-breaker substitution in Leu253 results in a transcriptionally inactive but highly stable protein variant. This is due to a feedback circuit between transcriptional activity of Gcn4 and its own stability, which depends on the Gcn4-controlled cyclin PCL5. Gcn4(L253G) reduces the expression of Pcl5 and therefore reduces its own degradation. This self-controlled buffer system to restrict transcriptional activity results in a reciprocal correlation between Gcn4 transcriptional activity and protein stability. (C) 2010 Elsevier Ltd. All rights reserved
Modeling dilative cardiomyopathy by induced pluripotent stem cell-derived cardiomyocytes from patients harboring a RBM20 mutation
No full textAssessing the influence of the genetic background on anthracycline induced cardiotoxicity with hiPSC derived cardiomyocytes
No full textDegradation of Saccharomyces cerevisiae Transcription Factor Gcn4 Requires a C-Terminal Nuclear Localization Signal in the Cyclin Pcl5
No full textPcl5 is a Saccharomyces cerevisiae cyclin that directs the phosphorylation of the general amino acid control transcriptional activator Gcn4 by the cyclin-dependent kinase (CDK) Pho85. Phosphorylation of Gcn4 by Pho85/Pcl5 initiates its degradation via the ubiquitin/proteasome system and is regulated by the availability of amino acids. In this study, we show that Pcl5 is a nuclear protein and that artificial dislocation of Pcl5 into the cytoplasm prevents the degradation of Gcn4. Nuclear localization of Pcl5 depends on the beta-importin Kap95 and does not require Pho85, Gcn4, or the CDK inhibitor Pho81. Pcl5 nuclear import is independent on the availability of amino acids and is mediated by sequences in its C-terminal domain. The nuclear localization signal is distinct from other functional domains of Pcl5. This is corroborated by a C-terminally truncated Pcl5 variant, which carries the N-terminal nuclear domain of Pho80. This hybrid is still able to fulfill Pcl5 function, whereas Pho80, which is another Pho85 interacting cyclin, does not mediate Gcn4 degradation
Assessing the influence of the genetic background on anthracycline induced cardiotoxicity with hiPSC derived cardiomyocytes
No full textModeling dilative cardiomyopathy by induced pluripotent stem cell-derived cardiomyocytes from patients harboring a RBM20 mutation
No full text
Generation of patient-specific induced pluripotent stem cells from plucked hair follicle-derived keratinocytes
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