Cyclin-dependent Kinase-9 Is a Component of the p300/GATA4 Complex Required for Phenylephrine-induced Hypertrophy in Cardiomyocytes

Sunagawa, Yoichi; Morimoto, Tatsuya; Takaya, Tomohide; Kaichi, Shinji; Wada, Hiromichi; Kawamura, Teruhisa; Fujita, Masatoshi; Shimatsu, Akira; Kita, Toru; Hasegawa, Koji

doi:10.1074/jbc.m109.070458

Cited by 68 publications

(66 citation statements)

References 51 publications

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“…16 Activation of p300 induces the acetylation of not only histone but also GATA4, increases its DNA-binding capacity and up-regulates the expression of hypertrophy-responsible genes. 17- 19 On the other hand, in transgenic mice that overexpress intact p300 in the heart, GATA4 acetylation and LV remodeling after myocardial infarction (MI) are augmented. Such augmentation did not occur in mice that overexpress mutant p300 lacking HAT activity.…”

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confidence: 99%

A Natural p300-Specific Histone Acetyltransferase Inhibitor, Curcumin, in Addition to Angiotensin-Converting Enzyme Inhibitor, Exerts Beneficial Effects on Left Ventricular Systolic Function After Myocardial Infarction in Rats

Sunagawa

Morimoto

Wada

et al. 2011

Circ J

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Circulation Journal Official Journal of the Japanese Circulation Society http://www. j-circ.or.jp eart failure (HF) is the final stage of all kinds of cardiovascular diseases, is associated with high mortality and morbidity and is increasing yearly in industrialized countries, 1,2 so it is crucial to prevent both its development and progression. In response to pressure or volume overload, the individual cardiomyocyte increases in size, which induces maladaptive hypertrophy, 3,4 leading to left ventricular (LV) dysfunction, remodeling and the development of HF. 5,6 Hemodynamic overload stimuli activate various neurohormonal factors, such as angiotensin II and endothelin-1. 7Based on the fact that these factors are involved in the development and deterioration of HF, agents such as angiotensinconverting enzyme inhibitors (ACEIs) are widely used as therapy in humans. Signals of these neurohormonal factors enter the cardiomyocytes via their extracellular receptors, finally reach the nuclei of cardiac myocytes and activate hypertrophy-responsive transcriptional factors such as GATA4, 8-10 MEF2 11 and SRF. 12 Activity of these factors are regulated by histone deacetylases and an intrinsic histone acetyltransferase (HAT), p300. Background: A natural p300-specific histone acetyltransferase (HAT) inhibitor, curcumin, may have therapeutic potential for heart failure. However, it is unclear whether curcumin exhibits beneficial additive or synergistic effects on conventional therapy with angiotensin-converting enzyme inhibitors (ACEIs).

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A Natural p300-Specific Histone Acetyltransferase Inhibitor, Curcumin, in Addition to Angiotensin-Converting Enzyme Inhibitor, Exerts Beneficial Effects on Left Ventricular Systolic Function After Myocardial Infarction in Rats

Sunagawa

Morimoto

Wada

et al. 2011

Circ J

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“…CDK9 was identified in investigations conducted on HIV as retroviruses hijack host transcription (19) and CDK9 inhibitors may serve as specific antiretroviral agents, particularly due to their involvement in preventing drug resistance. Myocardial hypertrophy is a risk factor for congestive heart failure that is characterized by the derepression of CDK9 activity (20). Therefore, CDK9 inhibitors may serve a therapeutic role in cardiology.…”

Section: Cdk9 and P-tefbmentioning

confidence: 99%

“…Owing to additional phosphorylation in the RNA pol II CTD at serine 2 by CDK9 activity, P-TEFb enables pol II to resume transcription subsequent to the promoter-proximal pause. In addition to RNA pol II, P-TEFb phosphorylates transcriptional complexes including the 5,6-dichloro-1-β-D-ribofuranosylbenzimidazole sensitivity-inducing factor and the negative elongation factor which are responsible for the promoter-proximal pausing of transcriptional machinery (20). P-TEFb primarily functions as in the elongation step, however, it has been identified in the pre-initiation transcription complex.…”

Section: Cdk9 and P-tefbmentioning

confidence: 99%

“…P-TEFb primarily functions as in the elongation step, however, it has been identified in the pre-initiation transcription complex. Although CDK9 and cyclin T1 individually do not possess any DNA-binding activity, the recruitment of P-TEFb to promoters is critical to activate gene expression (20). DNA sequence-specific transcription factors, such as nuclear factor κB (NF-κB), c-myc, c-fos and peroxisome proliferator-activated receptor γ, have been designated as P-TEFb-associated factors that recruit P-TEFb to their respective gene promoters.…”

Section: Cdk9 and P-tefbmentioning

confidence: 99%

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Cyclin-dependent kinase 9 may as a novel target in downregulating the atherosclerosis inflammation (Review)

et al. 2014

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Abstract. Inflammation is a key component of athero sclerosis. Genes coding for inflammatory or anti-inflammatory molecules are considered good candidates for estimating the risk of developing atherosclerosis. Cyclin-dependent kinase 9 (CDK9), the kinase of positive transcription elongation factor b (P-TEFb), is crucial in the cell cycle and apoptosis. Previous studies have focused on its inhibition of immune cells for the resolution of inflammation. Considering the effects of inflammation in the pathogenicity of atherosclerosis, decreasing inflammation through the inhibition of CDK9 may be useful for the prognosis of atherosclerosis. The aim of this review was to examine whether inhibition of the CDK9 monocyte may affect the process of inflammation by acting on the cytokine secretion and interacting with endothelial cells (ECs). Thus, CDK9 may be a novel target for the diagnosis and therapy of atherosclerosis. Contents1. Introduction 2. CDK9 and P-TEFb 3. CDK9 with T cells and monocytes 4. CDK9 and endothelium 5. CDK9 and inflammatory cytokines IntroductionAtherosclerosis is a complex vascular disease that usually begins in the first decade of life and is now recognized mainly as an inflammatory illness (1). It is a process characterized by the accumulation of lipids, mononuclear cells, fibrous components and calcium in the arteries (2). Vascular injury, recruitment of monocyte cells and infiltration of foam cells in combination with T lymphocytes, promotes lesion formation (2,3).Atherogenesis was traditionally considered a metabolic disease demonstrating arterial obstruction by fatty deposits in its wall (4). The current view is that atherogenesis involves highly specific biochemical and molecular responses with continuous interactions between different cellular players. Despite the presence of inflammatory reaction in each individual step of atherosclerosis from its beginning to a terminal manifestation, the cause-effect relationship of the two processes remains to be elucidated (4).Inflammation is crucial in the pathogenesis of atherosclerosis. Genes coding for inflammatory or anti-inflammatory molecules are considered potentially ideal candidates for estimating the risk of developing atherosclerosis (5-7). Accordingly, the production of high inflammatory molecules has been associated with atherosclerosis (8-11). Positive control of inflammation may play a protective role against atherosclerosis and is a potential therapeutic candidate for the prevention of atheroma formation.Cyclin-dependent kinases (CDKs) play an important role in the cell cycle and apoptosis. An increasing number of agents have been identified to interfere with the pathogenicity of atherosclerosis by targeting CDKS. Of these, CDK9 has been shown to exhibit marked characteristics in controlling inflammation (12). In a previous study (unpublished data), results of the 2-D proteomics analysis revealed that CDK9 was highly expressed in the serum of patients with atherosclerosis. The aim of the study was to analyze those results and identify t...

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“…17) Additionally, p300, which possesses intrinsic histone acetyltransferase activity, 18,19) induces GATA-4 acetylation, thereby enhancing its DNA binding and transcriptional activities. 20,21) While much is known about phosphorylation and acetylation of GATA-4, the molecular mechanism of GATA-4 ubiquitination, one of the critical post-translational modification processes, remains elusive, despite the fact that ubiquitination is involved in regulating bioactivities of diverse proteins.…”

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Erythropoietin Prevents Hypoxia-Induced GATA-4 Ubiquitination <i>via</i> Phosphorylation of Serine 105 of GATA-4

Jun

Shin

Kim

et al. 2013

Biological & Pharmaceutical Bulletin

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Erythropoietin (EPO), an essential hormone for erythropoiesis, can provide protection against myocardial ischemia/reperfusion (I/R) injury and hypoxic apoptosis. GATA-4 is a zinc finger transcription factor, and its activation and post-translational modification are essential components in the transcriptional response to hypoxia. GATA-4 has also been reported to play a role in the cellular mechanisms of EPO-induced myocardial protection against I/R injury. In this study, we aimed to investigate the influence of EPO on GATA-4 protein stability and post-translational modification under hypoxic conditions without reperfusion. EPO induced cell viability under long-term hypoxia. EPO significantly increased phosphorylation of GATA-4 via the extracellular signal-regulated kinase (ERK) signaling pathway and reduced hypoxia-induced GATA-4 ubiquitination, which enhanced GATA-4 stability under hypoxia. ERK activation by over-expression of constitutively active mitogen-activated protein kinase 1 (MEK1) strongly increased GATA-4 phosphorylation and its protein levels and decreased GATA-4 ubiquitination under hypoxia. Despite ERK activation, GATA-4 ubiquitination was not affected under hypoxia in a GATA-4-S105A mutant. Under hypoxic condition without reperfusion, EPO-induced ERK activation was associated with post-translational modification of GATA-4, mediated by enhancement of phosphorylation of GATA-4 at Ser-105. Subsequent attenuation of GATA-4 ubiquitination led to increases in GATA-4 protein stability, which resulted in increased cell viability under hypoxia.

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Cyclin-dependent Kinase-9 Is a Component of the p300/GATA4 Complex Required for Phenylephrine-induced Hypertrophy in Cardiomyocytes

Cited by 68 publications

References 51 publications

A Natural p300-Specific Histone Acetyltransferase Inhibitor, Curcumin, in Addition to Angiotensin-Converting Enzyme Inhibitor, Exerts Beneficial Effects on Left Ventricular Systolic Function After Myocardial Infarction in Rats

A Natural p300-Specific Histone Acetyltransferase Inhibitor, Curcumin, in Addition to Angiotensin-Converting Enzyme Inhibitor, Exerts Beneficial Effects on Left Ventricular Systolic Function After Myocardial Infarction in Rats

Cyclin-dependent kinase 9 may as a novel target in downregulating the atherosclerosis inflammation (Review)

Erythropoietin Prevents Hypoxia-Induced GATA-4 Ubiquitination <i>via</i> Phosphorylation of Serine 105 of GATA-4

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