Abstract 246: Acetylation of Vgll4 Regulates Hippo-yap Signaling and Postnatal Cardiac Growth

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Zhiqiang Lin ◽  
Haidong Guo ◽  
Sylvia Zohrabian ◽  
Yuan Cao ◽  
William T. Pu
Keyword(s):  
Heart Failure ◽  
Cell Cycle ◽  
Transcription Factor ◽  
Signaling Pathways ◽  
Binding Protein ◽  
Cardiac Regeneration ◽  
Cardiac Growth ◽  
Kinase Cascade

Binding of the transcription co-activator YAP with the transcription factor TEAD stimulates growth of the heart and other organs. Many signaling pathways, including the Hippo kinase cascade, converge to regulate YAP activity. However, less in known about the mechanisms that govern TEAD. YAP overexpression potently stimulates fetal cardiomyocyte (CM) proliferation, but YAP’s mitogenic potency declines postnatally, when mammalian cardiomyocytes largely exit the cell cycle. Here, we show that VGLL4, a CM-enriched TEAD1 binding protein, inhibits CM proliferation by limiting its binding to YAP and by targeting TEAD1 for degradation. VGLL4 antagonism of TEAD1 was governed by its acetylation at K225. Overexpression of VGLL4-K225R, an acetylation-refractory mutant, enhanced TEAD1 degradation, limited neonatal CM proliferation, and caused CM necrosis and heart failure. Our study defines an acetylation-mediated, VGLL4-dependent switch that regulates YAP-TEAD1 activity and restrains CM proliferation. These insights may enable more effective regulation of TEAD-YAP activity in applications ranging from cardiac regeneration to restraining cancer.

Abstract 13368: Acetylation of VGLL4 Tdu Domain Modulates Its Activity to Regulate Postnatal Cardiac Growth (Best of Basic Science Abstract)

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Zhiqiang Lin ◽  
Haidong Guo ◽  
Pingzhu Zhou ◽  
Qing Ma ◽  
Jin Zhang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Transcription Factor ◽  
Point Mutation ◽  
Basic Science ◽  
Binding Protein ◽  
Cardiac Regeneration ◽  
Hippo Signaling ◽  
Cardiac Growth ◽  
Neonatal Heart ◽  
Terminal Effector

Mammalian cardiomyocytes (CM) largely exit the cell cycle shortly after birth, limiting the heart’s capacity to recover from injury. The mechanisms that enforce neonatal CM cell cycle withdrawal are largely unknown. CM proliferation is stimulated by interaction of the co-activator YAP, the terminal effector of Hippo signaling, with the transcription factor TEAD1, but YAP’s mitogenic potency declines in the adult compared to fetal or newborn heart. Here we show that VGLL4, a CM-enriched TEAD1 binding protein, inhibits CM proliferation by competing with YAP for TEAD1 binding. Moreover, VGLL4 activity is regulated by acetylation of the lysine 225 (K225) residing in its first Tondu (Tdu) domain. Acetylation at K225 antagonized its interaction with TEAD1 in the neonatal heart. Overexpression of VGLL4 with a point mutation that blocks its acetylation enhanced VGLL4-TEAD1 interaction and limited CM proliferation, resulting in lethal cardiac hypoplasia. Our study defines a novel acetylation-mediated, VGLL4-dependent switch that regulates Hippo-YAP signaling and that restrains CM proliferation. These insights may enable more effective approaches to cardiac regeneration.

scholarly journals TATA-Binding Protein-Like Protein (TLP/TRF2/TLF) Negatively Regulates Cell Cycle Progression and Is Required for the Stress-Mediated G2 Checkpoint

2003 ◽  
Vol 23 (12) ◽  
pp. 4107-4120 ◽  
Author(s):  
Miho Shimada ◽  
Tomoyoshi Nakadai ◽  
Taka-aki Tamura
Keyword(s):  
Cell Cycle ◽  
Transcription Factor ◽  
Stress Response ◽  
Cell Growth ◽  
Cell Cycle Progression ◽  
Binding Protein ◽  
Tata Binding Protein ◽  
Cycle Progression ◽  
Stress Dependent ◽  
Dt40 Cells

ABSTRACT The TATA-binding protein (TBP) is a universal transcription factor required for all of the eukaryotic RNA polymerases. In addition to TBP, metazoans commonly express a distantly TBP-related protein referred to as TBP-like protein (TLP/TRF2/TLF). Although the function of TLP in transcriptional regulation is not clear, it is known that TLP is required for embryogenesis and spermiogenesis. In the present study, we investigated the cellular functions of TLP by using TLP knockout chicken DT40 cells. TLP was found to be dispensable for cell growth. Unexpectedly, TLP-null cells exhibited a 20% elevated cell cycle progression rate that was attributed to shortening of the G2 phase. This indicates that TLP functions as a negative regulator of cell growth. Moreover, we found that TLP mainly existed in the cytoplasm and was translocated to the nucleus restrictedly at the G2 phase. Ectopic expression of nuclear localization signal-carrying TLP resulted in an increase (1.5-fold) in the proportion of cells remaining in the G2/M phase and apoptotic state. Notably, TLP-null cells showed an insufficient G2 checkpoint when the cells were exposed to stresses such as UV light and methyl methanesulfonate, and the population of apoptotic cells after stresses decreased to 40%. These phenomena in G2 checkpoint regulation are suggested to be p53 independent because p53 does not function in DT40 cells. Moreover, TLP was transiently translocated to the nucleus shortly (15 min) after stress treatment. The expression of several stress response and cell cycle regulatory genes drifted in a both TLP- and stress-dependent manner. Nucleus-translocating TLP is therefore thought to work by checking cell integrity through its transcription regulatory ability. TLP is considered to be a signal-transducing transcription factor in cell cycle regulation and stress response.

Role of GSK-3 in Cardiac Health: Focusing on Cardiac Remodeling and Heart Failure

2021 ◽  
Vol 22 ◽  
Author(s):  
Ubaid Tariq ◽  
Shravan Kumar Uppulapu ◽  
Sanjay K Banerjee
Keyword(s):  
Heart Failure ◽  
Cell Cycle ◽  
Cardiac Development ◽  
Glycogen Synthase ◽  
Cardiac Regeneration ◽  
Negative Regulator ◽  
Cell Cycle Regulators ◽  
Cardiomyocyte Proliferation ◽  
Gsk 3Β

: Glycogen synthase kinase 3 (GSK-3) is a ubiquitously expressed serine/threonine kinase and was first identified as a regulator of glycogen synthase enzyme and glucose homeostasis. It regulates cellular processes like cell proliferation, metabolism, apoptosis and development. Recent findings suggest that GSK-3 is required to maintain the normal cardiac homeostasis that regulates cardiac development, proliferation, hypertrophy and fibrosis. GSK-3 is expressed as two isoforms, α and β. Role of GSK-3α and GSK-3β in cardiac biology is well documented. Both isoforms have common as well as isoform-specific functions. Human data also suggests that GSK-3β is downregulated in hypertrophy and heart failure, and acts as a negative regulator. Pharmacological inhibition of GSK-3α and GSK-3β leads to the endogenous cardiomyocyte proliferation and cardiac regeneration by inducing the upregulation of cell cycle regulators, which results in cell cycle re-entry and DNA synthesis. It was found that cardiac specific knockout (KO) of GSK-3α retained cardiac function, inhibited cardiovascular remodelling and restricted scar expansion during ischemia. Further, knockout of GSK-3α decreases cardiomyocyte apoptosis and enhances its proliferation. However, GSK-3β KO also results in hypertrophic myopathy due to cardiomyocyte hyper-proliferation. Thus GSK-3 inhibitors are named as a double-edged sword because of their beneficial and off target effects. This review focuses on the isoform specific functions of GSK-3 that will help in better understanding about the role of GSK-3α and GSK-3β in cardiac biology and pave a way for the development of new isoform specific GSK-3 modulator for the treatment of ischemic heart disease, cardiac regeneration and heart failure.

Spi-1/PU.1 participates in erythroleukemogenesis by inhibiting apoptosis in cooperation with Epo signaling and by blocking erythroid differentiation

Blood ◽  
2006 ◽  
Vol 109 (7) ◽  
pp. 3007-3014 ◽  
Author(s):  
Pauline Rimmelé ◽  
Olivier Kosmider ◽  
Patrick Mayeux ◽  
Françoise Moreau-Gachelin ◽  
Christel Guillouf
Keyword(s):  
Cell Cycle ◽  
Transcription Factor ◽  
Signaling Pathways ◽  
Signaling Pathway ◽  
Erythroid Differentiation ◽  
Differentiation Process ◽  
Erythroid Cells ◽  
Knock Down ◽  
Apoptotic Death ◽  
Differentiation Block

Abstract Overexpression of the transcription factor Spi-1/PU.1 in mice leads to acute erythroleukemia characterized by a differentiation block at the proerythroblastic stage. In this study, we made use of a new cellular system allowing us to reach graded expression of Spi-1 in preleukemic cells to dissect mechanisms of Spi-1/PU-1 in erythroleukemogenesis. This system is based on conditional production of 1 or 2 spi-1–interfering RNAs stably inserted into spi-1 transgenic proerythroblasts. We show that Spi-1 knock-down was sufficient to reinstate the erythroid differentiation program. This differentiation process was associated with an exit from the cell cycle. Evidence is provided that in the presence of erythropoietin (Epo), Spi-1 displays an antiapoptotic role that is independent of its function in blocking erythroid differentiation. Apoptosis inhibited by Spi-1 did not involve activation of the Fas/FasL signaling pathway nor a failure to activate Epo receptor (EpoR). Furthermore, we found that reducing the Spi-1 level yields to ERK dephosphorylation and increased phosphorylation of AKT and STAT5, suggesting that Spi-1 may affect major signaling pathways downstream of the EpoR in erythroid cells. These findings reveal 2 distinct roles for Spi-1 during erythroleukemogenesis: Spi-1 blocks the erythroid differentiation program and acts to impair apoptotic death in cooperation with an Epo signaling.

Abstract 021: Extended Proliferation Capacity of Cardiomyocytes is Insufficient to Complete Cardiac Regeneration in Mice with a Mutation of Cardiac Myosin Binding Protein C

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Gregory M Fomovsky ◽  
Joseph B Gannon ◽  
Kimberly K Schaefer ◽  
Jianming Jiang ◽  
Hiroko Wakimoto ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Protein C ◽  
Binding Protein ◽  
Cardiac Regeneration ◽  
Brdu Incorporation ◽  
Cardiac Myosin ◽  
Proliferation Capacity ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Myosin Binding

Introduction: Adult mammalian cardiac regeneration rate is inadequate to compensate for the loss of myocardium following injury. One-day old (P1) mice fully regenerate myocardium after ventricular apex resection by division of cardiomyocytes (CMs). This regeneration ability is lost by P7. While CMs of a P1 mouse are mostly mononuclear, CMs withdraw from cell cycle and become mostly binuclear in the first post-natal week. CMs in mice with a mutation of a sarcomeric cardiac myosin-binding protein C (MyBP-C t/t ) have an extended proliferating capacity. In MyBP-C t/t mice, there are more CMs per ventricle and a significant number of CMs remain mononuclear compared to WT. Hypothesis: The loss of regeneration potential during the first post-natal week in WT mice is a result of rigid sarcomeric structure of maturing CMs, and a mutation of sarcomeric MyBP-C would extend the regenerative capacity of CMs beyond P1. Methods: We performed apical resections on P10 MyBP-C t/t and WT mice with sham-operated controls (n=61 of 118 survived surgery). For the resection surgery, neonates were anesthetized on ice, causing transient sedation, apnea and asystole. We assessed cardiac regeneration over two weeks by measuring cell cycle activity: Ki67 and pH3 expressions, and BrdU incorporation. Results: All cell cycle activity markers in MyBP-C t/t CMs were significantly higher than in WT. At 7 days-post resection (dpr) the number of BrdU-positive CM nuclei per 40X field was (mean±SD): 1.8±1.2 in MyBP-C t/t resections (n=4), 0.7±0.3 in MyBP-C t/t shams (n=5), 0.3±0.3 in WT resections (n=3), and 0.2±0.2 in WT shams (n=3). However, an increase in cell cycle activity in MyBP-C t/t resected hearts was not significant compared to MyBP-C t/t sham controls. Interestingly, using VonKossa silver staining, we observed pronounced dystrophic calcifications due to CM necrosis in MyBP-C t/t resected hearts only. The calcifications filled the resected area and were positive for cardiac troponin and proliferation markers as early as 3dpr, suggesting that proliferating CMs underwent necrosis and aborted regeneration. Conclusion: An extended proliferation capacity of MyBP-C t/t CMs beyond the first post-natal week is insufficient for complete cardiac regeneration following apical resection.

scholarly journals The TRF2 General Transcription Factor Is a Key Regulator of Cell Cycle Progression

2020 ◽  
Author(s):  
Adi Kedmi ◽  
Anna Sloutskin ◽  
Natalie Epstein ◽  
Lital Gasri-Plotnitsky ◽  
Debby Ickowicz ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Flow Cytometry ◽  
Transcription Factor ◽  
Cell Cycle Progression ◽  
Binding Protein ◽  
Cyclin E ◽  
Mass Spectrometry Analysis ◽  
Related Factor ◽  
Cycle Progression ◽  
General Transcription Factor

AbstractTRF2 (TATA-box-binding protein-related factor 2) is an evolutionarily conserved general transcription factor that is essential for embryonic development of Drosophila melanogaster, C. elegans, zebrafish and Xenopus. Nevertheless, the cellular processes that are regulated by TRF2 are largely underexplored.Here, using Drosophila Schneider cells as a model, we discovered that TRF2 regulates cell cycle progression. Using flow cytometry, high-throughput microscopy and advanced imaging-flow cytometry, we demonstrate that TRF2 knockdown regulates cell cycle progression and exerts distinct effects on G1 and specific mitotic phases. RNA-seq analysis revealed that TRF2 regulates the expression of Cyclin E and the mitotic cyclins, Cyclin A, Cyclin B and Cyclin B3, but not Cyclin D or Cyclin C. To identify proteins that could account for the observed regulation of these cyclin genes, we searched for TRF2-interacting proteins. Interestingly, mass spectrometry analysis of TRF2-containing complexes identified GFZF, a nuclear glutathione S-transferase implicated in cell cycle regulation, and Motif 1 binding protein (M1BP). Furthermore, available ChIP-exo data revealed that TRF2, GFZF and M1BP co-occupy the promoters of TRF2-regulated genes. Using RNAi to knockdown the expression of either M1BP, GFZF, TRF2 or their combinations, we demonstrate that although GFZF and M1BP interact with TRF2, it is TRF2, rather than GFZF or M1BP, that is the main factor regulating the expression of Cyclin E and the mitotic cyclins. Taken together, our findings uncover a critical and unanticipated role of a general transcription factor as a key regulator of cell cycle.

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