The KLF Family of Transcriptional Regulators in Cardiomyocyte Proliferation and Differentiation

Nemer, Mona; Horb, Marko E.

doi:10.4161/cc.6.2.3718

Cited by 62 publications

(62 citation statements)

References 37 publications

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“…In pulmonary smooth muscle cells, GATA4 appears to be important for cell proliferation, and overexpression of a repressor form of GATA4 suppresses cyclin D2 expression (73), which supports the direct activation of Cyclin D2 by GATA4 observed in our studies. Similarly, GATA1 induces the sustained expression of cyclin D1 in a myeloid cell line (77), and GATA4 cooperates with the Kruppel-like factor KLF13 to activate Cyclin D1 in Xenopus laevis (46). All of these studies, taken together with the work presented here, support a model in which GATA factors may function generally as regulators of the cell cycle in multiple tissues.…”

Section: Discussionsupporting

confidence: 67%

GATA4 Is a Direct Transcriptional Activator of Cyclin D2 and Cdk4 and Is Required for Cardiomyocyte Proliferation in Anterior Heart Field-Derived Myocardium

Rojas

Kong

Agarwal

et al. 2008

Molecular and Cellular Biology

114

115

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The anterior heart field (AHF) comprises a population of mesodermal progenitor cells that are added to the nascent linear heart to give rise to the majority of the right ventricle, interventricular septum, and outflow tract in mammals and birds. The zinc finger transcription factor GATA4 functions as an integral member of the cardiac transcription factor network in the derivatives of the AHF. In addition to its role in cardiac differentiation, GATA4 is also required for cardiomyocyte replication, although the transcriptional targets of GATA4 required for proliferation have not been previously identified. In the present study, we disrupted Gata4 function exclusively in the AHF and its derivatives. Gata4 AHF knockout mice die by embryonic day 13.5 and exhibit hypoplasia of the right ventricular myocardium and interventricular septum and display profound ventricular septal defects. Loss of Gata4 function in the AHF results in decreased myocyte proliferation in the right ventricle, and we identified numerous cell cycle genes that are dependent on Gata4 by microarray analysis. We show that GATA4 is required for cyclin D2, cyclin A2, and Cdk4 expression in the right ventricle and that the Cyclin D2 and Cdk4 promoters are bound and activated by GATA4 via multiple consensus GATA binding sites in each gene's proximal promoter. These findings establish Cyclin D2 and Cdk4 as direct transcriptional targets of GATA4 and support a model in which GATA4 controls cardiomyocyte proliferation by coordinately regulating numerous cell cycle genes.The cardiac lineage in mammals is initially specified from the anterior lateral mesoderm at embryonic day 7.5 (E7.5) in the mouse. The nascent cardiac mesoderm migrates anteriolaterally and fuses ventrally in the embryo to form a linear tube. The linear tube elongates through the addition of cells from the second heart field to the arterial and venous poles (1,12,28). A more restricted, anterior subset of these cells are added only to the arterial pole from the pharyngeal and splanchnic mesoderm. These cells, referred as the anterior heart field (AHF), give rise to the outflow tract, right ventricle, and ventricular septum (1,9,11,27,81). As cells from the AHF are added, the heart bends toward the ventral side, undergoes rightward looping, expands dramatically, and is eventually remodeled into the mature, four-chambered organ (13, 66).Embryonic cardiomyocytes differentiate as they continue to proliferate (48, 52). At early stages in development, cardiomyocytes have a high proliferation rate, which decreases progressively in late gestation (67). The high rate of cell cycle activity during the early stages of cardiomyocyte differentiation contributes to the growth of the future chambers within the linear tube during looping morphogenesis (42). The trabecular myocardium has a high rate of proliferation at this stage. As ventricular volumes increase, the trabeculations become compressed within the ventricular wall, resulting in a significant increase in the thickness of the compact myocardium (...

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Section: Discussionsupporting

confidence: 67%

GATA4 Is a Direct Transcriptional Activator of Cyclin D2 and Cdk4 and Is Required for Cardiomyocyte Proliferation in Anterior Heart Field-Derived Myocardium

Rojas

Kong

Agarwal

et al. 2008

Molecular and Cellular Biology

114

115

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“…KLF13 (Krüppel-like factor 13) is a zinc finger transcription factor known to play a role in proliferation, differentiation, cell cycle progression, and apoptosis [Chen et al, 2001;Kaczynski et al, 2003;Nemer and Key Words FGFR3 ؒ KLF13 ؒ miRNA ؒ Oral cancer Abstract KLF13 and FGFR3 have important cellular functions and each is believed to play a role in cancer. KLF13 is a transcription factor required for the expression of several oncogenes.…”

mentioning

confidence: 99%

Overexpression of <i>KLF13</i> and <i>FGFR3</i> in Oral Cancer Cells

Henson

Gollin

2010

Cytogenet Genome Res

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KLF13 and FGFR3 have important cellular functions and each is believed to play a role in cancer. KLF13 is a transcription factor required for the expression of several oncogenes. FGFR3 is a fibroblast growth factor receptor that initiates a signaling cascade leading to the activation of numerous cellular pathways. Here we show that KLF13 and FGFR3 are overexpressed in oral cancer cells. We also show that artificially reducing cellular levels of KLF13 and FGFR3 decreases cell proliferation and increases sensitivity to ionizing radiation. These data suggest that KLF13 and FGFR3 contribute to malignancy in oral cancer cells and may be useful biomarkers for early detection and possible targets for therapy.

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“…Recently, it has been reported that KLF family transcriptional factors regulates versatile type of differentiation [22].…”

Section: Discussionmentioning

confidence: 99%

Regulation of Skeletal Muscle Differentiation by Akt

Woo¹,

Yun²,

Kim³

et al. 2012

Journal of Life Science

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Akt plays an important role in a variety of cellular physiologies such as growth, proliferation, and differentiation. In skeletal muscle, Akt has been implicated in regulating regeneration, hypertrophy, and atrophy. In this study, the role of Akt has been examined during skeletal muscle differentiation. Culturing C2C12 myoblasts under low serum (1% horse serum) and high density converted cell morphology from a round shape to an elongated and multi-nucleated shape. Morphological changes were initiated from day 2 of differentiation. In addition, the expression of both myogenin G and myogenin D was elevated from day 2 of differentiation. Skeletal muscle differentiation was abolished by silencing Akt1 or Akt2, but was significantly enhanced by the over-expression of either Akt1 or Akt2. The activation of Akt was observed from day 2 of differentiation and disappeared after day 7. The expression of krüppel-like factor 4 was observed from day 6 of differentiation. Moreover, this expression was blocked in cells silencing either Akt1 or Akt2. In addition, the promoter activity of krüppel-like factor 4 was significantly reduced in cells silencing Akt1 or Akt2. These results suggest that Akt regulates skeletal muscle differentiation through the regulation of krüppel-like factor 4 expression.

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The KLF Family of Transcriptional Regulators in Cardiomyocyte Proliferation and Differentiation

Cited by 62 publications

References 37 publications

GATA4 Is a Direct Transcriptional Activator of Cyclin D2 and Cdk4 and Is Required for Cardiomyocyte Proliferation in Anterior Heart Field-Derived Myocardium

GATA4 Is a Direct Transcriptional Activator of Cyclin D2 and Cdk4 and Is Required for Cardiomyocyte Proliferation in Anterior Heart Field-Derived Myocardium

Overexpression of <i>KLF13</i> and <i>FGFR3</i> in Oral Cancer Cells

Regulation of Skeletal Muscle Differentiation by Akt

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