Changes in E2F Complexes Containing Retinoblastoma Protein Family Members and Increased Cyclin-dependent Kinase Inhibitor Activities During Terminal Differentiation of Cardiomyocytes

Flink, Irwin L.; Oana, Shinji; Maitra, Niranjan; Bahl, Joseph J.; Morkin, Eugene

doi:10.1006/jmcc.1997.0620

Cited by 71 publications

(51 citation statements)

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“…Cardiomyocyte mitotic arrest is associated with downregulation of G1/S and G2/M cyclins and cyclin-dependent kinases (CDKs) and upregulation of cell cycle inhibitors (Engel et al, 2005;Flink et al, 1998;Poolman and Brooks, 1998). The overexpression of cyclins D1 and D2 and cyclin A2 can stimulate cardiomyocyte DNA synthesis or mitosis, respectively, in adult mice (Chaudhry et al, 2004;Pasumarthi et al, 2005;Soonpaa et al, 1997), and the deletion of p130 (Rbl2) and Rb (Rb1) causes cardiomyocytes to re-enter the cell cycle (Sdek et al, 2011).…”

Section: The Regulation Of Cell Cycle Withdrawalmentioning

confidence: 99%

Building and re-building the heart by cardiomyocyte proliferation

2016

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The adult human heart does not regenerate significant amounts of lost tissue after injury. Rather than making new, functional muscle, human hearts are prone to scarring and hypertrophy, which can often lead to fatal arrhythmias and heart failure. The most-cited basis of this ineffective cardiac regeneration in mammals is the low proliferative capacity of adult cardiomyocytes. However, mammalian cardiomyocytes can avidly proliferate during fetal and neonatal development, and both adult zebrafish and neonatal mice can regenerate cardiac muscle after injury, suggesting that latent regenerative potential exists. Dissecting the cellular and molecular mechanisms that promote cardiomyocyte proliferation throughout life, deciphering why proliferative capacity normally dissipates in adult mammals, and deriving means to boost this capacity are primary goals in cardiovascular research. Here, we review our current understanding of how cardiomyocyte proliferation is regulated during heart development and regeneration.

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Section: The Regulation Of Cell Cycle Withdrawalmentioning

confidence: 99%

Building and re-building the heart by cardiomyocyte proliferation

2016

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“…Recent studies have shown that Apaf-1 levels in post-mitotic cells such as cardiomyocytes and sympathetic neurons are markedly reduced (as compared to mitotic cells) [108,109,116], resulting in a significant decrease in apoptosome activity. The reduced activity of E2F1 [30], which is a transcriptional regulator of Apaf-1 [93] in terminally differentiated cardiomyocytes, is likely to contribute to the marked reduction of Apaf-1 in these cells. Given the reduced apoptosome activity (resulting from low levels of Apaf-1), endogenous XIAP has a greater inhibitory impact on apoptosis in post-mitotic cells.…”

Section: Apoptosismentioning

confidence: 99%

Rho kinase in the regulation of cell death and survival

Shi

Wei

2007

Arch. Immunol. Ther. Exp.

219

183

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SummaryRho kinase (ROCK) belongs to a family of serine/threonine kinases that are activated via interaction with Rho GTPases. ROCK is involved in a wide range of fundamental cellular functions such as contraction, adhesion, migration, and proliferation. Recent studies have shown that ROCK plays an important role in the regulation of apoptosis in various cell types and animal disease models. Two ROCK isoforms, ROCK1 and ROCK2, are assumed to be function redundant, based largely on kinase construct overexpression, and chemical inhibitors (Y27632 and fasudil), which inhibit both ROCK1 and ROCK2. Gene targeting and RNA interference approaches allow further dissection of distinct cellular, physiological and patho-physiological functions of the two ROCK isoforms. This review, based on recent molecular, cellular and animal studies, focuses on the current understanding of ROCK signaling in the regulation of apoptosis and highlights the new findings from recently generated ROCK-deficient mice.

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“…3E). Increases in p21 levels have been reported to be correlated with the exit from cell cycle that occurs in the neonatal heart and with differentiation of cultured cardiomyocytes (Flink et al 1998;Koh et al 1998). Thus, it is logical to think that up-regulation of p21 might result in a block in cell proliferation that could account for the thinned myocardium observed in SMRT −/− and FOXP1 −/− embryos.…”

Section: Smrt/foxp1 Repressive Functions Genes and Development 741mentioning

confidence: 99%

Cooperative regulation in development by SMRT and FOXP1

Jepsen¹,

Gleiberman²,

Shi³

et al. 2008

Genes Dev.

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A critical aspect of mammalian development involves the actions of dedicated repressors/corepressors to prevent unregulated gene activation programs that would initiate specific cell determination events. While the role of NCoR/SMRT corepressors in nuclear receptor actions is well documented, we here report that a previously unrecognized functional interaction between SMRT and a forkhead protein, FOXP1, is required for cardiac growth and regulation of macrophage differentiation. Our studies demonstrate that SMRT and FOXP1 define a functional biological unit required to orchestrate specific programs critical for mammalian organogenesis, linking developmental roles of FOX to a specific corepressor.Supplemental material is available at http://www.genesdev.org.Received November 27, 2007; revised version accepted January 18, 2008. Although activation of transcription has long been recognized as an essential component of gene regulation during development, the critical role of transcriptional repression programs is apparent from the pluripotent stem cell to terminal differentiation events. Nuclear receptors, including retinoic acid and thyroid hormone receptors (RAR and T 3 R), regulate development through both ligand-dependent activation and active repression by unliganded nuclear receptors (Glass and Rosenfeld 2000), and their ability to actively repress transcription in the absence of their cognate ligands is conferred by their interaction with SMRT or with the highly related corepressor NCoR (Chen and Evans 1995;Horlein et al. 1995). NCoR and SMRT also confer transcriptional repression to many additional members of the nuclear receptor superfamily, as well as on a variety of unrelated transcription factors, at least in part due to corecruitment of histone deacetylase proteins (HDACs) (Privalsky 2001;Jepsen and Rosenfeld 2002;Jones and Shi 2003).The forkhead family of transcription factors, which includes over a hundred genes in several species named for the forkhead-box (FOX) DNA-binding domain, has been characterized as both transcriptional activators and repressors (for review, see Wijchers et al. 2006). While all four FoxP family members function as transcriptional repressors, the mechanism of this repression remains largely uncharacterized, although FoxP3 has been shown to be capable of interacting with HDAC proteins (Li et al. 2007). Gene deletion studies have revealed that FOXP1 mutant mice have defects in cardiac morphogenesis, a thin ventricular myocardial compact zone, and lack of proper ventricular septation, which together result in embryonic death at embryonic day 14.5 (E14.5) (Wang et al. 2004). Interestingly, maintaining the proper balance of histone acetylation/deacetylation is critical for proper cardiac development and growth (Backs and Olson 2006;Montgomery et al. 2007), leading us to consider potential links between FOXP1 and recruitment of specific corepressor complexes.Here we report that deletion of the gene encoding the corepressor SMRT resulted in specific developmental abnormalities in...

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Changes in E2F Complexes Containing Retinoblastoma Protein Family Members and Increased Cyclin-dependent Kinase Inhibitor Activities During Terminal Differentiation of Cardiomyocytes

Cited by 71 publications

References 0 publications

Building and re-building the heart by cardiomyocyte proliferation

Building and re-building the heart by cardiomyocyte proliferation

Rho kinase in the regulation of cell death and survival

Cooperative regulation in development by SMRT and FOXP1

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