Atsushi Yokoyama

Tohoku University | Tohokudai · Department of Molecular Endocrinology

Hepatocyte nuclear factor 4α (HNF4α) has an essential role in controlling the expression of variety of genes involved in key metabolic pathways including gluconeogenesis in the liver. Though mechanistic and physiological significance of proliferator-activated receptor-gamma co-activator-1α (PGC-1α) for HNF4α-mediated transcriptional activation mode...

Primary aldosteronism (PA) is a common cause of secondary hypertension. PA induces damage to cardiovascular and renal blood vessels. Therefore, PA is regarded as a problem because it increases the risk of stroke, cardiomyopathy, kidney disease, etc. Aldosterone-producing adenomas (APA) are one of the major causes of PA, and gene mutations are often...

Hypertension is a frequently observed complication among obese patients. Recently, undetermined adipocyte-derived factor(s) have been recognized as one of the causes of the obesity-related hypertension independent of angiotensin (A) II. In this study, we aim to identify the undetermined adipocyte-derived factor(s) that stimulate aldosterone synthas...

Diabetic nephropathy (DN) is the main cause of chronic kidney disease (CKD), and is characterized by elevated urinary albumin to creatinine ratio (UACR) and serum creatinine, and decreased glomerular filtration rate. Anti hypertensive agents are used for DN treatment, however, the effects of these drugs are insufficient, and the establishment of mo...

Primary aldosteronism (PA) is a refractory hypertension that accounts for approximately 5%-10% of hypertensive patients. aldosterone-producing adenomas and idiopathic hyperaldosteronism are known causes of PA. In aldosterone-producing adenomas, depolarization due to somatic mutations of ion channels in adrenocortical cells is considered the cause o...

Primary aldosteronism (PA) is a common cause of secondary hypertension. PA induces damage to cardiovascular and renal blood vessels. Therefore, PA is regarded as a problem because it increases the risk of stroke, cardiomyopathy, kidney disease, etc. Aldosterone-producing adenomas (APA) are one of the major causes of PA, and gene mutations are often...

Hepatocyte nuclear factor 4α (HNF4α) has an essential role in controlling the expression of variety of genes involved in key metabolic pathways including gluconeogenesis in the liver. Though mechanistic and physiological significance of proliferator-activated receptor-gamma co-activator-1α (PGC-1α) for HNF4α-mediated transcriptional activation mode...

Diabetic nephropathy (DN) is the main cause of chronic kidney disease (CKD) and is characterized by elevated urinary albumin to creatinine ratio (UACR) and serum creatinine, and decreased glomerular filtration rate. Anti hypertensive agents are used for DN treatment, however, the effects of these drugs are insufficient, and the establishment of mor...

Primary aldosteronism (PA) is considered the most common form of secondary hypertension, which is associated with excessive aldosterone secretion in the adrenal cortex. The cause of excessive aldosterone secretion is the induction of aldosterone synthase gene (CYP11B2) expression by depolarization of adrenocortical cells. In this study, we found th...

Hepatocyte nuclear factor 4α (HNF4α) has essential roles in controlling the expression of a variety of genes involved in key metabolic pathways, including gluconeogenesis in the liver. The mechanistic and physiological significance of peroxisome proliferator-activated receptor gamma co-activator-1α (PGC-1α) for HNF4α-mediated transcriptional activa...

Glucose is not only the energy fuel for most cells, but also the signaling molecule which affects gene expression via carbohydrate response element binding protein (ChREBP), a Mondo family transcription factor. In response to high glucose conditions, ChREBP regulates glycolytic and lipogenic genes by binding to carbohydrate response elements (ChoRE...

Prostate cancer antigen 3 (PCA3) is a prostate cancer-specific long noncoding RNA (lncRNA). Here, we report that lncRNA PCA3 plays a role in prostate cancer progression that is mediated by nucleoplasmic lamins. PCA3 interacts with the C-terminal region of lamina-associated polypeptide (LAP) 2α. The C-terminal region of LAP2α includes tumor suppress...

The androgen receptor (AR) plays an essential role in the development of prostate cancer and androgen deprivation therapy is used as a first-line treatment for prostate cancer. However, under androgen deprivation therapy, castration-resistant prostate cancer inevitably arises, suggesting that the interacting transcriptional coregulators of AR are p...

Androgens have a robust effect on skeletal muscles to increase muscle mass and strength. Whereas, the molecular mechanism of androgen/Androgen Receptor (AR) action on muscle strength is still not well-known, especially for the regulation of sarcomeric genes. In this study, we generated an androgen-induced hypertrophic model mice, myofiber-specific...

Angiotensin II (Ang II) is a well-known peptide that maintains the balance of electrolytes in the higher vertebrates. Ang II stimulation in the adrenal gland induces the synthesis of mineralocorticoids, mainly aldosterone, through the up-regulation of aldosterone synthase (CYP11B2) gene expression. Additionally, it has been reported that Ang II act...

Aldosterone is synthesized in the adrenal by the aldosterone synthase CYP11B2. Although the control of CYP11B2 expression is important to maintain the mineral homeostasis, its overexpression induced by the depolarization-induced calcium (Ca²⁺) signaling activation has been reported to increase the synthesis of aldosterone in primary aldosteronism (...

Checkpoint kinase 1 (CHK1) plays a key role in genome surveillance and integrity throughout the cell cycle. Selective inhibitors of CHK1 (CHK1i) are undergoing clinical evaluation for various human malignancies, including neuroblastoma. Recently, we reported that CHK1i, PF-477736, induced a p53-mediated DNA damage response. As a result, the cancer...

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Carbohydrate response element binding protein (ChREBP), a glucose responsive transcription factor, mainly regulates expression of genes involved in glucose metabolism and lipogenesis. Recently, ChREBP is speculated to be involved in the onset and progression of diabetic nephropathy (DN). However, there exists no report regarding the localization an...

Background and Objective Obesity is highly complicated by hypertension and hyperglycemia. In particular, it has been proposed that obesity-related hypertension is caused by adipocyte-derived factors that are recognized as undetermined proteins secreted from adipocytes. Adipocyte-derived factors have been known to be related to aldosterone secretion...

In Drosophila, some neurons develop sex-specific neurites that contribute to dimorphic circuits for sex-specific behavior. As opposed to the idea that the sexual dichotomy in transcriptional profiles produced by a sex-specific factor underlies such sex differences, we discovered that the sex-specific cleavage confers the activity as a sexual-fate i...

Aldosterone is synthesized in zona glomerulosa of adrenal cortex in response to angiotensin II. This stimulation transcriptionally induces expression of a series of steroidogenic genes such as HSD3B and CYP11B2 via NR4A (nuclear receptor subfamily 4 group A) nuclear receptors and ATF (activating transcription factor) family transcription factors. N...

Although therapeutic effects of the peroxisome proliferator-activated receptor gamma (PPAR- γ ) agonists rosiglitazone and pioglitazone against Cushing’s disease have been reported, their effects are still controversial and inconsistent. We therefore examined the effects of a novel PPAR- γ agonist, MEKT1, on Pomc expression/ACTH secretion using mur...

Figure S1: MEKT1-mediated effect of PPAR-γ mRNA expression in AtT20 cells in a dose-dependent manner. AtT20 cells were treated with MEKT1 (1 nM, 10 nM, 100 nM, 1 μM, or 10 μM) or 0.1% DMSO (vehicle control) for 24 hours. Data are expressed as percentages (100%) of control. Data represent mean ± SEM (n = 4). ∗∗P < 0.01 versus control. Figure S2: inv...

Posttranslational modification (PTM) of proteins is used to regulate protein activity and stability. Histone PTMs are regarded as some of the most important, as they can directly regulate gene expression through chromatin reorganization. Recently, histone proteins were found to undergo succinylation, adding to other well-known PTMs such as acetylat...

The effects of retinoids on adrenal aldosterone synthase gene (CYP11B2) expression and aldosterone secretion are still unknown. We therefore examined the effects of nuclear retinoid X receptor (RXR) pan-agonist PA024 on CYP11B2 expression, aldosterone secretion and blood pressure, to elucidate its potential as a novel anti-hypertensive drug. We dem...

Aldosterone synthase is the key rate‐limiting enzyme in adrenal aldosterone production, and induction of its gene (CYP11B2) results in the progression of hypertension. As hypertension is a frequent complication among patients with diabetes, we set out to elucidate the link between diabetes mellitus and hypertension. We examined the effects of high...

Background: Heparan sulphate proteoglycan (HSPG) is present in the glomerular basement membrane (GBM) and is thought to play a major role in the glomerular charge barrier. Reductions and structural alterations of HSPG are observed in different types of kidney diseases accompanied by proteinuria. However, their causal relations remain unknown. Met...

Retinoids are natural and synthetic derivatives of retinol, otherwise known as vitamin A. Retinoids bind to several classes of proteins including retinoid-binding proteins and retinoid nuclear receptors leading to the activation of specific regulatory elements of DNA that are involved in regulating cell growth, differentiation, and apoptosis. Sever...

CYP11B2 is a key enzyme involved in the synthesis of the mineralocorticoid aldosterone. CYP11B2 expression in the adrenal glands is controlled by the renin-angiotensin system (RAS), and plays an important role in the maintenance of electrolyte metabolism in higher organisms. Abnormal overexpression of CYP11B2 results in the disruption of mineral ba...

The mechanism of the negative regulation of proopiomelanocortin gene (Pomc) by glucocorticoids (Gcs) is still unclear in many points. Here, we demonstrated the involvement of neurogenic differentiation factor 1 (NeuroD1) in the Gc-mediated negative regulation of Pomc. Murine pituitary adrenocorticotropic hormone (ACTH) producing corticotroph tumor-...

Purpose: It is still unknown in many points of the mechanism of negative regulation of Proopiomelanocortin (Pomc) gene by glucocorticoids. In this study, we demonstrated the involvement of Neurogenic differentiation factor D1 (NeuroD1) in glucocorticoid mediated negative regulation of Pomc gene in AtT20 cell, which is a murine pituitary ACTH (Adren...

Various retinoid X receptor (RXR) agonists have recently been developed, and some of them have shown anti-tumor effects both in vivo and in vitro. However, there has been no report showing the effects of RXR agonists on Cushing's disease, which is caused by excessive ACTH secretion in a corticotroph tumor of the pituitary gland. Therefore, we exami...

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DNA methylation is closely involved in the regulation of cellular differentiation, including chondrogenic differentiation of mesenchymal stem cells. Recent studies showed that Ten-eleven translocation (TET) family proteins converted 5-methylcytosine (5mC) to 5-hydroxymethylcytosine, 5-formylcytosine and 5carboxylcytosine by oxidation. These reactio...

Estrogen-related receptor α (ERRα) is a member of the nuclear receptor superfamily and regulates many physiological functions, including mitochondrial biogenesis and lipid metabolism. ERRα enhances the transactivation function without endogenous ligand by associating with coactivators such as peroxisome proliferator-activated receptor γ coactivator...

Cushing's disease is a disorder caused by excessive ACTH secretion from a corticotroph tumor of the pituitary gland. Although its standard therapy is a transsphenoidal surgery, innovation of novel medical treatments for the disease is urgently necessary. Retinoic acid (RA) has been reported to suppress adrenocorticotropic hormone (ACTH) secretion i...

Posttranslational modification (PTM) of proteins is critical for various cellular processes. However, there are few studies examining PTMs in specific proteins using unbiased approaches. Here we report the attempt to identify the PTMs in peroxisome proliferator-activated receptor γ (PPARγ) proteins using our previously established PTM analysis syst...

Regulation of spatiotemporal gene expression in higher eukaryotic cells is critical for the precise and orderly development of undifferentiated progenitors into committed cell types of the adult. It is well known that dynamic epigenomic regulation (including chromatin remodeling and histone modifications by transcriptional coregulator complexes) is...

We generated a stable H295R cell line expressing aldosterone synthase gene (CYP11B2) promoter/luciferase chimeric reporter construct that is highly sensitive to angiotensin II (AII) and potassium, and defined AII receptor blocker (ARB) effects. In the presence of AII, all ARBs suppressed AII-induced CYP11B2 transcription. However, telmisartan alone...

Gene expression is controlled by alterations in the epigenome, including DNA methylation and histone modification. Recently, it was reported that 5-methylcytosine (5mC) is converted to 5-hydroxymethylcytosine (5hmC) by proteins in the ten-eleven translocation (TET) family. This conversion is believed to be part of the mechanism by which methylated...

Androgens play pivotal roles in the regulation of male development and physiological processes, particularly in the male reproductive system. Most biological effects of androgens are mediated by the action of nuclear androgen receptor (AR). AR acts as a master regulator of downstream androgen-dependent signaling pathway networks. This ligand-depend...

Osteoclastogenesis is a highly regulated process governed by diverse classes of regulators. Among them, nuclear factor of activated T-cells calcineurin-dependent 1 (NFATc1) is the primary osteoclastogenic transcription factor, and its expression is transcriptionally induced during early osteoclastogenesis by receptor activation of nuclear factor κB...

Chromatin reorganization is governed by multiple post-translational modifications of chromosomal proteins and DNA. These histone modifications are reversible, dynamic events that can regulate DNA-driven cellular processes. However, the molecular mechanisms that coordinate histone modification patterns remain largely unknown. In metazoans, reversibl...

Liganded nuclear receptors (NRs) are DNA-binding transcription factors that control the transcription of target genes. Such NRs exert their transcriptional functions via ligand binding-induced interactions with a number of coregulator complexes to reorganize chromatin state. Intensive investigation of NR coregulator complexes has revealed that, bes...

To investigate the role of post-translational modifications (PTMs) in the hepatocyte nuclear factor 4α (HNF4α)-mediated transcription, we took a comprehensive survey of PTMs in HNF4α protein by mass-spectrometry and identified totally 8 PTM sites including newly identified ubiquitilation and acetylation sites. To assess the impact of identified PTM...

Osteoblasts and adipocytes are derived from common mesenchymal progenitor cells. The bone loss of osteoporosis is associated with altered progenitor differentiation from an osteoblastic to an adipocytic lineage. cDNA microarrays and quantitative real-time PCR (Q-PCR) were carried out in a differentiating mouse stromal osteoblastic cell line, Kusa 4...

Members of the nuclear steroid/thyroid hormone receptor (NR) gene superfamily are DNA-binding transcription factors that regulate target genes in a spatiotemporal manner, depending on the promoter context. In vivo observations of ligand responses in NR-mediated gene regulation led to the identification of ligand-dependent coregulators that directly...

The methylation states of histone lysine residues are regarded as significant epigenetic marks governing transcriptional regulation. A number of histone demethylases containing a jumonji C (JmjC) domain have been recognized; however, their properties remain to be investigated. Here, we show that KIAA1718, a PHF2/PHF8 subfamily member, possesses his...

Estrogen-related receptor α (ERRα) is a member of the nuclear receptor superfamily and regulates many physiological functions, including mitochondrial biogenesis and lipid metabolism. ERRα enhances the transactivation function without endogenous ligand by associating with coactivators such as peroxisome proliferator-activated receptor γ coactivator...

O-glycosylation has emerged as an important modification of nuclear proteins, and it appears to be involved in gene regulation. Recently, we have shown that one of the histone methyl transferases (MLL5) is activated through O-glycosylation by O-GlcNAc transferase (OGT). Addition of this monosaccharide is essential for forming a functional complex....

Changes in the environment of a cell precipitate extracellular signals and sequential cascades of protein modification and elicit nuclear transcriptional responses. However, the functional links between intracellular signaling-dependent gene regulation and epigenetic regulation by chromatin-modifying proteins within the nucleus are largely unknown....

TLX is an orphan nuclear receptor (also called NR2E1) that regulates the expression of target genes by functioning as a constitutive transrepressor. The physiological significance of TLX in the cytodifferentiation of neural cells in the brain is known. However, the corepressors supporting the transrepressive function of TLX have yet to be identifie...

Signet-ring cell carcinoma is one of the most malignant tumors, classified histologically as a poorly differentiated adenocarcinoma. The ErbB2/ErbB3 complex is often constitutively activated, which suggests that the ErbB2/ErbB3 signaling pathway may be important for malignancy of this tumor. However, the mechanism underlying this activation has not...

Photoreceptor cell-specific nuclear receptor (PNR) (NR2E3) acts as a sequence-specific repressor that controls neuronal differentiation in the developing retina. We identified a novel PNR co-repressor, Ret-CoR, that is expressed in the developing retina and brain. Biochemical purification of Ret-CoR identified a multiprotein complex that included E...