Early stage-specific inhibitions of cardiomyocyte differentiation and expression of Csx/Nkx-2.5 and GATA-4 by phosphatidylinositol 3-kinase inhibitor LY294002

Naito, Atsuhiko T.; Tominaga, Aki; Oyamada, Masahito; Oyamada, Yumiko; Shiraishi, Isao; Monzen, Koshiro; Komuro, Issei; Takamatsu, Tetsuro

doi:10.1016/s0014-4827(03)00378-1

Cited by 41 publications

(28 citation statements)

References 41 publications

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“…18 We have recently reported that phosphatidylinositol 3-kinase (PI3K) pathway is required when mesodermal cells start to express cardiac transcription factors. 19 In this study, we demonstrated that canonical Wnt pathway is required and sufficient for commitment of cardiomyocytes and clarified that PI3K pathway is involved in cardiomyocyte differentiation by crosstalk with canonical Wnt pathway.…”

mentioning

confidence: 63%

Phosphatidylinositol 3-Kinase–Akt Pathway Plays a Critical Role in Early Cardiomyogenesis by Regulating Canonical Wnt Signaling

Naito

Akazawa

Takano

et al. 2005

Circulation Research

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112

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Abstract-We have recently reported that activation of phosphatidylinositol 3-kinase (PI3K) plays a critical role in the early stage of cardiomyocyte differentiation of P19CL6 cells. We here examined molecular mechanisms of how PI3K is involved in cardiomyocyte differentiation. DNA chip analysis revealed that expression levels of Wnt-3a were markedly increased and that the Wnt/␤-catenin pathway was activated temporally during the early stage of cardiomyocyte differentiation of P19CL6 cells. Activation of the Wnt/␤-catenin pathway during this period was required and sufficient for cardiomyocyte differentiation of P19CL6 cells. Inhibition of the PI3K/Akt pathway suppressed the Wnt/␤-catenin pathway by activation of glycogen synthase kinase-3␤ (GSK-3␤) and degradation of ␤-catenin. Suppression of cardiomyocyte differentiation by inhibiting the PI3K/Akt pathway was rescued by forced expression of a nonphosphorylated, constitutively active form of ␤-catenin. These results suggest that the PI3K pathway regulates cardiomyocyte differentiation through suppressing the GSK-3␤ activity and maintaining the Wnt/␤-catenin activity.

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mentioning

confidence: 63%

Phosphatidylinositol 3-Kinase–Akt Pathway Plays a Critical Role in Early Cardiomyogenesis by Regulating Canonical Wnt Signaling

Naito

Akazawa

Takano

et al. 2005

Circulation Research

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112

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“…Except for GATA, the proteins that recognize these elements in luteal cells are still under investigation. Because GATA is recognized by GATA-4 in luteal cells and because the activity of this transcription factor can be modulated by Akt [126], it is possible to postulate that the PRL/PI3/Akt/GATA-4 pathway is involved in the activation of the aromatase gene in the corpus luteum. Bars represent aromatase mRNA levels in corpora lutea of rats on different days of pregnancy.…”

Section: Signaling and Genomic Integrationmentioning

confidence: 99%

Aromatase expression in the ovary: Hormonal and molecular regulation

2008

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Summary-Estrogens are synthesized by the aromatase enzyme encoded by the Cyp19a1 gene, which contains an unusually large regulatory region. In most mammals, aromatase expression is under the control of two distinct promoters a gonad-and a brain-specific promoter. In humans, this gene contains 10 tissue-specific promoters that are alternatively used in various cell types and tumors. Each promoter is regulated by a distinct set of regulatory sequences and transcription factors that bind to these specific sequences. The cAMP/PKA/CREB pathway is considered to be the primary signaling cascade through which the gonad Cyp19 promoter is regulated. Very interestingly, in rat luteal cells, the proximal promoter is not controlled in a cAMP dependent manner. Strikingly, these cells express aromatase at high levels similar to those found in preovulatory follicles, suggesting that alternative and powerful mechanisms control aromatase expression in luteal cells and that the rat corpus luteum represents an important paradigm for understanding alternative controls of the aromatase gene. Here, the molecular and cellular mechanisms controlling the expression of the aromatase gene in granulosa and luteal cells are discussed.

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“…It was initially reported that inhibition of PI3K attenuates cardiomyocyte differentiation in embryonic stem (ES) cells, suggesting that PI3K pathway is essential for cardiomyocyte differentiation (Klinz et al 1999). Using P19CL6, a clonal derivative of P19 teratocarcinoma cell line that differentiate into cardiomyocytes in response to DMSO treatment, it was reported that Akt is activated during cardiomyocyte differentiation, and that treatment with PI3K or Akt inhibitors results in attenuation of P19CL6 differentiation into cardiomyocytes (Naito et al 2003). PI3K inhibition in DMSO-treated P19CL6 cells is associated with down-regulation of early cardiac marker genes such as Nkx-2.5 and GATA-4, suggesting that the PI3K-Akt pathway is critical during early-stage cardiomyocyte differentiation.…”

Section: Regulation Of Cardiomyocyte Differentiation and Embryonic Hementioning

confidence: 99%

Regulation of cardiac growth and coronary angiogenesis by the Akt/PKB signaling pathway

Shiojima¹,

Walsh²

2006

Genes Dev.

323

260

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Postnatal growth of the heart is primarily achieved through hypertrophy of individual myocytes. Cardiac growth observed in athletes represents adaptive or physiological hypertrophy, whereas cardiac growth observed in patients with hypertension or valvular heart diseases is called maladaptive or pathological hypertrophy. These two types of hypertrophy are morphologically, functionally, and molecularly distinct from each other. The serine/threonine protein kinase Akt is activated by various extracellular stimuli in a phosphatidylinositol-3 kinasedependent manner and regulates multiple aspects of cellular functions including survival, growth and metabolism. In this review we will discuss the role of the Akt signaling pathway in the heart, focusing on the regulation of cardiac growth, contractile function, and coronary angiogenesis. How this signaling pathway contributes to the development of physiological/pathological hypertrophy and heart failure will also be discussed.Growth of the heart during embryonic development occurs primarily through proliferation of cardiac myocytes. However, cardiac myocytes withdraw from the cell cycle soon after birth, and subsequent growth of the heart during postnatal development is achieved predominantly through hypertrophy rather than hyperplasia of individual myocytes (Pasumarthi and Field 2002;Olson and Schneider 2003). In fact, there is almost a threefold increase in cardiac myocyte diameter in humans during development from infants to adults (Hudlicka and Brown 1996). Cardiac growth during normal postnatal development or the hypertrophy observed in trained athletes is referred to as "physiological," and it is characterized by normal or enhanced contractile function and normal architecture and organization of cardiac structure (Richey and Brown 1998). On the other hand, cardiac hypertrophy is also observed in patients with pathological conditions such as hypertension, myocardial infarction, and valvular heart diseases. This type of cardiac growth is called "pathological" hypertrophy, and is frequently associated with contractile dysfunction, interstitial fibrosis, and re-expression of fetal-type cardiac genes such as atrial natriuretic peptide and ␤-myosin heavy chain (Molkentin and Dorn 2001;Frey and Olson 2003). These data indicate that pathological cardiac hypertrophy is morphologically and molecularly distinct from physiological cardiac hypertrophy. The pathological form of cardiac hypertrophy is initially recognized as an adaptive response to increased external load, because increased wall stress induced by overload is attenuated by the increase in wall thickness. However, increased cardiac mass is clinically associated with increased morbidity and mortality (Levy et al. 1990), and a sustained overload eventually leads to contractile dysfunction and heart failure through poorly understood mechanisms (Molkentin and Dorn 2001;Frey and Olson 2003). In addition, hypertrophy of individual myocyte is a common feature of failing myocardium (Gerdes et al. 1992). Thus, pathological ...

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Early stage-specific inhibitions of cardiomyocyte differentiation and expression of Csx/Nkx-2.5 and GATA-4 by phosphatidylinositol 3-kinase inhibitor LY294002

Cited by 41 publications

References 41 publications

Phosphatidylinositol 3-Kinase–Akt Pathway Plays a Critical Role in Early Cardiomyogenesis by Regulating Canonical Wnt Signaling

Phosphatidylinositol 3-Kinase–Akt Pathway Plays a Critical Role in Early Cardiomyogenesis by Regulating Canonical Wnt Signaling

Aromatase expression in the ovary: Hormonal and molecular regulation

Regulation of cardiac growth and coronary angiogenesis by the Akt/PKB signaling pathway

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