Abstract 64: Meis1 Is a Key Regulator of Postnatal Cardiomyocyte Cell Cycle Arrest

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Fatih Kocabas ◽  
Ahmed I Mahmoud ◽  
Shalini Muralidhar ◽  
Enzo Porrello ◽  
Eric Olson ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Transcriptional Activation ◽  
Gene Array ◽  
Mouse Heart ◽  
Cardiomyocyte Proliferation ◽  
Mammalian Heart ◽  
Cycle Arrest ◽  
Complete Regeneration

Heart failure is a costly and deadly disease affecting over 5 million Americans. The inability of the adult mammalian heart to regenerate following injury lies at core of the pathophysiology of heart failure. We recently showed that the neonatal mammalian heart is capable of complete regeneration following resection of the entire ventricular apex. Moreover, our preliminary data indicate that the neonatal mouse heart is also capable of complete regeneration following ischemic myocardial infarction. In both these types of injury, the regenerative response is associated with robust proliferation of cardiomyocytes without significant hypertrophy or fibrosis. Genetic fate mapping studies demonstrated that the majority of newly formed cardiomyocytes originated from pre-existing cardiomyocytes. In an effort to determine the mechanism of cardiomyocytes cell cycle arrest after the first week of life, we performed a gene array after cardiac injury at multiple post-natal timepoints. This enabled us to identify Meis1 as a potential regulator of neonatal cardiomyocyte proliferation. Meis1, which belongs to the TALE family of homeodomain transcription factors, is required for normal hematopoiesis and cardiac development. While Meis1 has been extensively studied in the hematopoietic system, little is known about its role in the heart. Our results indicate that Meis1 expression and nuclear localization in the post-natal cardiomyocytes coincides with cell cycle arrest. To further explore this pattern, we generated a cardiomyocyte-specific Meis1 knockout mouse, and showed that loss of Meis1 results in robust cardiomyocyte proliferation in the adult heart. Moreover, we identified p16 and p21; two synergistic cyclin dependent kinase inhibitors that induce arrest at all three cell cycle checkpoints, as potential targets for transcriptional activation by Meis1. These results identify Meis1 as a key regulator of post-natal cardiomyocyte cell cycle arrest, and a potential therapeutic target for cardiac regeneration.

Abstract 20492: Mlf1 Regulates Myocyte Proliferation in Postnatal Hearts

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Shalini Muralidhar ◽  
Feng Xiao ◽  
Suwannee Thet ◽  
Hesham Sadek
Keyword(s):  
Cell Cycle ◽  
Transcription Factors ◽  
Cell Cycle Arrest ◽  
Molecular Mechanisms ◽  
Gene Array ◽  
Bhlh Transcription Factor ◽  
Cardiomyocyte Proliferation ◽  
Regenerative Capacity ◽  
Cycle Arrest ◽  
Endogenous Expression

Lower vertebrates, such as newt and zebrafish, retain a robust cardiac regenerative capacity following injury. Although adult mammals lack this cardiac regenerative potential, there is ample interest in understanding how heart regeneration occurs, and to reawaken this process in adult humans. Recently, we showed that mice are capable of regenerating their hearts shortly after birth following injury. This regenerative response is associated with robust proliferation of cardiomyocytes without significant hypertrophy or fibrosis. However, this regenerative capacity is lost by 7 days postnatally, coinciding with cell cycle arrest. In an effort to determine the mechanism of cardiomyocytes cell cycle arrest after the first week of life, we performed a gene array after cardiac injury at multiple post-natal time points. This enabled us to identify a number of transcription factors that are differentially expressed during this postnatal window. We recently reported that one of these transcription factors Meis1 regulates postnatal cell cycle arrest of cardiomyocytes. Furthermore, Myeloid leukemia factor 1 (Mlf1), a bhlh transcription factor that has not been previously studied in the heart has similar dysregulated pattern following injury. Our preliminary data with in-vitro knockdown of Mlf1 in cardiomyocyte resulted in 2-fold increase in cardiomyocyte proliferation. Furthermore, immunohistochemistry results indicated that the endogenous expression and nuclear localization of Mlf1 in the post-natal cardiomyocytes coincides with cell cycle arrest. To explore this pattern, we generated a cardiomyocyte-specific Mlf1 knockout mouse, and showed that loss of Mlf1 results in robust cardiomyocyte proliferation in postnatal hearts (P14). Additionally, we confirmed previous reports that Mlf1 regulates p53 and induces cell cycle arrest by induction of CDK inhibitors like p21 and p57 in these Mlf1 KO mice. This suggests a role of Mlf1 in promoting reactivation of injured myocardium through induction of cardiomyocyte proliferation. These findings will further provide evidences of molecular mechanisms involved in the dormant regenerative capacity in adult mammals that can be a potential target of therapeutic approaches.

scholarly journals Triptolide abrogates growth of colon cancer and induces cell cycle arrest by inhibiting transcriptional activation of E2F

2015 ◽  
Vol 95 (6) ◽  
pp. 648-659 ◽  
Author(s):  
Amanda R Oliveira ◽  
Georg Beyer ◽  
Rohit Chugh ◽  
Steven J Skube ◽  
Kaustav Majumder ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Colon Cancer ◽  
Cell Cycle Arrest ◽  
Transcriptional Activation ◽  
Cycle Arrest

scholarly journals Differential activation of target cellular promoters by p53 mutants with impaired apoptotic function.

1996 ◽  
Vol 16 (9) ◽  
pp. 4952-4960 ◽  
Author(s):  
R L Ludwig ◽  
S Bates ◽  
K H Vousden
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Dna Sequences ◽  
Transcriptional Activation ◽  
Cellular Response ◽  
Kinase Inhibitor ◽  
Cell Types ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Cycle Arrest ◽  
P53 Tumor Suppressor Protein

The p53 tumor suppressor protein is a sequence-specific transcriptional activator, a function which contributes to cell cycle arrest and apoptosis induced by p53 in appropriate cell types. Analysis of a series of p53 point mutants has revealed the potential for selective loss of the ability to transactivate some, but not all, cellular p53-responsive promoters. p53 175P and p53 181L are tumor-derived p53 point mutants which were previously characterized as transcriptionally active. Both mutants retained the ability to activate expression of the cyclin-dependent kinase inhibitor p2lcip1/waf1, and this activity correlated with the ability to induce a G1 cell cycle arrest. However, an extension of this survey to include other p53 targets showed that p53 175P was defective in the activation of p53-responsive sequences derived from the bax promoter and the insulin-like growth factor-binding protein 3 gene (IGF-BP3) promoter, while p53 181L showed loss of the ability to activate a promoter containing IGF-BP3 box B sequences. Failure to activate transcription was also reflected in the reduced ability of the mutants to bind the p53-responsive DNA sequences present in these promoters. These specific defects in transcriptional activation correlated with the impaired apoptotic function displayed by these mutants, and the results suggest that activation of cell cycle arrest genes by p53 can be separated from activation of genes with a role in mediating the p53 apoptotic response. The cellular response to p53 activation may therefore depend, at least in part, on which group of p53-responsive genes become transcriptionally activated.

scholarly journals Sympathetic nerve activity promotes cardiomyocyte cell-cycle arrest and binucleation

2017 ◽  
Author(s):  
Li Chen ◽  
Alexander Y. Payumo ◽  
Kentaro Hirose ◽  
Rachel B. Bigley ◽  
Jonathan Lovas ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Sympathetic Nerve ◽  
Adrenergic Receptors ◽  
Sympathetic Nerve Activity ◽  
Cardiomyocyte Proliferation ◽  
Nerve Activity ◽  
Cycle Arrest ◽  
Β Adrenergic Receptors

ABSTRACTAdult mammalian hearts typically have little capacity to regenerate after injuries such as myocardial infarction. In contrast, neonatal mice during the first week of life possess an incredible ability to regenerate their hearts, though this capacity is lost shortly after birth. The physiological triggers mediating this transition remains poorly understood. In this study, we demonstrate that sympathetic nerve activity promotes cardiomyocyte cell-cycle arrest and binucleation. In mice hearts lacking sympathetic nerve inputs, we observe increased mononucleated cardiomyocyte numbers and elevated cardiomyocyte proliferation. Additionally, increased cardiomyocyte mononucleation and proliferation are observed in mice with genetic and pharmacological inhibition of β-adrenergic receptors (βARs), which mediate sympathetic nerve signaling. Using in vitro cultures of neonatal cardiomyocytes, we demonstrate that activation of β-adrenergic receptors results in decreased cardiomyocyte proliferation that is mediated through cyclic AMP-dependent protein kinase (PKA) signaling. Taken together, these results suggest that sympathetic nerve activity may play a role in limiting the ability of mammalian hearts to regenerate by restricting cardiomyocyte proliferation and promoting cytokinesis failure leading to multinucleation.

scholarly journals Alternative splicing of pericentrin contributes to cell cycle control in cardiomyocytes

2021 ◽  
Author(s):  
Jakob Steinfeldt ◽  
Robert Becker ◽  
Silvia Vergarajauregui ◽  
Felix B Engel
Keyword(s):  
Cell Cycle ◽  
Alternative Splicing ◽  
Cell Cycle Arrest ◽  
Cell Cycle Control ◽  
Ectopic Expression ◽  
Cell Number ◽  
Cardiomyocyte Proliferation ◽  
C2c12 Myoblasts ◽  
Cycle Arrest ◽  
Heterologous System

Induction of cardiomyocyte proliferation is a promising option to regenerate the heart. Thus, it is important to elucidate mechanisms that contribute to the cell cycle arrest of mammalian cardiomyocytes. Here, we assessed the contribution of the pericentrin (Pcnt) S isoform to the cell cycle arrest in postnatal cardiomyocytes. Immunofluorescence staining of Pcnt isoforms combined with siRNA-mediated depletion indicates that Pcnt S preferentially localizes to the nuclear envelope, while the Pcnt B isoform is enriched at centrosomes. This is further supported by the localization of ectopically expressed FLAG-tagged Pcnt S and Pcnt B in postnatal cardiomyocytes. Analysis of centriole configuration upon Pcnt depletion revealed that Pcnt B but not Pcnt S is required for centriole cohesion. Importantly, ectopic expression of Pcnt S induced centriole splitting in a heterologous system, ARPE-19 cells, and was sufficient to impair DNA synthesis in C2C12 myoblasts. Moreover, Pcnt S depletion enhanced serum-induced cell cycle re-entry in postnatal cardiomyocytes. Analysis of mitosis, binucleation rate, and cell number suggests that Pcnt S depletion promotes progression of postnatal cardiomyocytes through the cell cycle resulting in cell division. Collectively, our data indicate that alternative splicing of Pcnt contributes to the establishment of cardiomyocyte cell cycle arrest shortly after birth.

scholarly journals A microRNA program controls the transition of cardiomyocyte hyperplasia to hypertrophy and stimulates mammalian cardiac regeneration

2021 ◽  
Author(s):  
Andrea Raso ◽  
Ellen Dirkx ◽  
Vasco Sampaio-Pinto ◽  
Hamid el Azzouzi ◽  
Ryan J. Cubero ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Gene Delivery ◽  
Cell Cycle Arrest ◽  
Regulatory Function ◽  
Viral Gene ◽  
Postnatal Life ◽  
Mouse Heart ◽  
Cell Cycle Regulators ◽  
Induce Cell Cycle Arrest ◽  
Cycle Arrest

Myocardial regeneration is restricted to early postnatal life, when mammalian cardiomyocytes still retain the ability to proliferate. The molecular cues that induce cell cycle arrest of neonatal cardiomyocytes towards terminally differentiated adult heart muscle cells remain obscure. Here we report that the miR-106b∼25 cluster is higher expressed in the early postnatal myocardium and decreases in expression towards adulthood, especially under conditions of overload, and orchestrates the transition of cardiomyocyte hyperplasia towards cell cycle arrest and hypertrophy by virtue of its targetome. In line, gene delivery of miR-106b∼25 to the mouse heart provokes cardiomyocyte proliferation by targeting a network of negative cell cycle regulators including E2f5, Cdkn1c, Ccne1 and Wee1. Conversely, gene-targeted miR-106b∼25 null mice display spontaneous hypertrophic remodeling and exaggerated remodeling to overload by derepression of the prohypertrophic transcription factors Hand2 and Mef2d. Taking advantage of the regulatory function of miR-106b∼25 on cardiomyocyte hyperplasia and hypertrophy, viral gene delivery of miR-106b∼25 provokes nearly complete regeneration of the adult myocardium after ischemic injury. Our data demonstrate that exploitation of conserved molecular programs can enhance the regenerative capacity of the injured heart.

scholarly journals Glucocorticoid receptor-mediated cell cycle arrest is achieved through distinct cell-specific transcriptional regulatory mechanisms.

1997 ◽  
Vol 17 (6) ◽  
pp. 3181-3193 ◽  
Author(s):  
I Rogatsky ◽  
J M Trowbridge ◽  
M J Garabedian
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Transcriptional Activation ◽  
Growth Arrest ◽  
Receptor Activation ◽  
Regulatory Mechanisms ◽  
Activation Domain ◽  
Transcriptional Activation Domain ◽  
Cycle Arrest ◽  
U2os Cells

Glucocorticoids inhibit proliferation of many cell types, but the events leading from the activated glucocorticoid receptor (GR) to growth arrest are not understood. Ectopic expression and activation of GR in human osteosarcoma cell lines U2OS and SAOS2, which lack endogenous receptors, result in a G1 cell cycle arrest. GR activation in U2OS cells represses expression of the cyclin-dependent kinases (CDKs) CDK4 and CDK6 as well as their regulatory partner, cyclin D3, leading to hypophosphorylation of the retinoblastoma protein (Rb). We also demonstrate a ligand-dependent reduction in the expression of E2F-1 and c-Myc, transcription factors involved in the G1-to-S-phase transition. Mitogen-activated protein kinase, CDK2, cyclin E, and the CDK inhibitors (CDIs) p27 and p21 are unaffected by receptor activation in U2OS cells. The receptor's N-terminal transcriptional activation domain is not required for growth arrest in U2OS cells. In Rb-deficient SAOS2 cells, however, the expression of p27 and p21 is induced upon receptor activation. Remarkably, in SAOS2 cells that express a GR deletion derivative lacking the N-terminal transcriptional activation domain, induction of CDI expression is abolished and the cells fail to undergo ligand-dependent cell cycle arrest. Similarly, murine S49 lymphoma cells, which, like SAOS2 cells, lack Rb, require the N-terminal activation domain for growth arrest and induce CDI expression upon GR activation. These cell-type-specific differences in receptor domains and cellular targets linking GR activation to cell cycle machinery suggest two distinct regulatory mechanisms of GR-mediated cell cycle arrest: one involving transcriptional repression of G1 cyclins and CDKs and the other involving enhanced transcription of CDIs by the activated receptor.

scholarly journals Forkhead Transcription Factors Are Critical Effectors of Cell Death and Cell Cycle Arrest Downstream of PTEN

2000 ◽  
Vol 20 (23) ◽  
pp. 8969-8982 ◽  
Author(s):  
Noriaki Nakamura ◽  
Shivapriya Ramaswamy ◽  
Francisca Vazquez ◽  
Sabina Signoretti ◽  
Massimo Loda ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Transcription Factors ◽  
Cell Cycle Arrest ◽  
Transcriptional Activation ◽  
Active Form ◽  
Forkhead Transcription Factors ◽  
Cycle Arrest ◽  
In Cells ◽  
Constitutively Active

ABSTRACT PTEN acts as a tumor suppressor, at least in part, by antagonizing phosphoinositide 3-kinase (PI3K)/Akt signaling. Here we show that Forkhead transcription factors FKHRL1 and FKHR, substrates of the Akt kinase, are aberrantly localized to the cytoplasm and cannot activate transcription in PTEN-deficient cells. Restoration of PTEN function restores FKHR to the nucleus and restores transcriptional activation. Expression of a constitutively active form of FKHR that cannot be phosphorylated by Akt produces the same effect as reconstitution of PTEN on PTEN-deficient tumor cells. Specifically, activated FKHR induces apoptosis in cells that undergo PTEN-mediated cell death and induces G1 arrest in cells that undergo PTEN-mediated cell cycle arrest. Furthermore, both PTEN and constitutively active FKHR induce p27KIP1 protein but not p21. These data suggest that Forkhead transcription factors are critical effectors of PTEN-mediated tumor suppression.

scholarly journals Transcriptional activation of Odf2/Cenexin by cell cycle arrest and the stress activated signaling pathway (JNK pathway)

2013 ◽  
Vol 1833 (6) ◽  
pp. 1338-1346 ◽  
Author(s):  
Nadin Pletz ◽  
Anja Medack ◽  
Eva Maria Rieß ◽  
Kefei Yang ◽  
Zahra Basir Kazerouni ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Signaling Pathway ◽  
Transcriptional Activation ◽  
Jnk Pathway ◽  
Cycle Arrest

Rb regulates C/EBPβ-DNA-binding activity during 3T3-L1 adipogenesis

2004 ◽  
Vol 286 (2) ◽  
pp. C349-C354 ◽  
Author(s):  
Kathryn A. Cole ◽  
Anne W. Harmon ◽  
Joyce B. Harp ◽  
Yashomati M. Patel
Keyword(s):  
Cell Cycle ◽  
Dna Binding ◽  
Cell Cycle Arrest ◽  
Transcriptional Activation ◽  
Binding Activity ◽  
Luciferase Reporter ◽  
Luciferase Reporter Gene ◽  
Dna Binding Activity ◽  
Cycle Arrest ◽  
Rb Phosphorylation

Two pathways are initiated upon 3T3-L1 preadipocyte differentiation: the reentry of cells into the cell cycle and the initiation of a cascade of transcriptional events that “prime” the cell for differentiation. The “priming” event involves the synthesis of members of the CCAAT/enhancer binding protein (C/EBP) family of transcription factors. However, the relationship between these two pathways is unknown. Here we report that in the 3T3-L1 preadipocytes induced to differentiate, cell cycle progression and the initiation of differentiation are linked by a cell cycle-dependent Rb-C/EBPβ interaction. Cell cycle arrest in G1 by l-mimosine inhibited differentiation-induced C/EBPβ-DNA-binding activity and Rb phosphorylation. However, cell cycle arrest after the G1/S transition by aphidicolin or nocodazole did not prevent C/EBPβ-DNA-binding activity or Rb phosphorylation. Furthermore, hypophosphorylated Rb and C/EBPβ coimmunoprecipitated, whereas phosphorylated Rb and C/EBPβ did not. Electrophoretic mobility shift assays demonstrated that recombinant hypophosphorylated Rb decreased C/EBPβ-DNA-binding activity and that Rb overexpression inhibited C/EBPβ-induced transcriptional activation of a C/EBPα-promoter-luciferase reporter gene. We conclude that C/EBPβ-DNA-binding activity is regulated by its interaction with hypophosphorylated Rb, thereby linking the progression of the cell cycle to the initiation of differentiation during 3T3-L1 adipogenesis.

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