12 results on '"Yoshiaki Soejima"'
Search Results
2. Oxytocin enhances progesterone production with upregulation of BMP-15 activity by granulosa cells
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Koichiro Yamamoto, Yasuhiro Nakano, Nahoko Iwata, Yoshiaki Soejima, Atsuhito Suyama, Toru Hasegawa, and Fumio Otsuka
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Biophysics ,Cell Biology ,Molecular Biology ,Biochemistry - Published
- 2023
3. Mutual Effects of Orexin and Bone Morphogenetic Proteins on Gonadotropin Expression by Mouse Gonadotrope Cells
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Yoshiaki Soejima, Nahoko Iwata, Nanako Nakayama, Shinichi Hirata, Yasuhiro Nakano, Koichiro Yamamoto, Atsuhito Suyama, Kohei Oguni, Takahiro Nada, Satoshi Fujisawa, and Fumio Otsuka
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Orexins ,bone morphogenetic protein (BMP) ,clock ,gonadotropin ,orexin ,pituitary ,Organic Chemistry ,Luteinizing Hormone, beta Subunit ,General Medicine ,Catalysis ,Computer Science Applications ,Gonadotropin-Releasing Hormone ,Inorganic Chemistry ,Mice ,Pituitary Gland ,Bone Morphogenetic Proteins ,Follicle Stimulating Hormone, beta Subunit ,Animals ,RNA, Messenger ,Physical and Theoretical Chemistry ,Molecular Biology ,Gonadotropins ,Spectroscopy - Abstract
Orexin plays a key role in the regulation of sleep and wakefulness and in feeding behavior in the central nervous system, but its receptors are expressed in various peripheral tissues including endocrine tissues. In the present study, we elucidated the effects of orexin on pituitary gonadotropin regulation by focusing on the functional involvement of bone morphogenetic proteins (BMPs) and clock genes using mouse gonadotrope LβT2 cells that express orexin type 1 (OX1R) and type 2 (OX2R) receptors. Treatments with orexin A enhanced LHβ and FSHβ mRNA expression in a dose-dependent manner in the absence of GnRH, whereas orexin A in turn suppressed GnRH-induced gonadotropin expression in LβT2 cells. Orexin A downregulated GnRH receptor expression, while GnRH enhanced OX1R and OX2R mRNA expression. Treatments with orexin A as well as GnRH increased the mRNA levels of Bmal1 and Clock, which are oscillational regulators for gonadotropin expression. Of note, treatments with BMP-6 and -15 enhanced OX1R and OX2R mRNA expression with upregulation of clock gene expression. On the other hand, orexin A enhanced BMP receptor signaling of Smad1/5/9 phosphorylation through upregulation of ALK-2/BMPRII among the BMP receptors expressed in LβT2 cells. Collectively, the results indicate that orexin regulates gonadotropin expression via clock gene expression by mutually interacting with GnRH action and the pituitary BMP system in gonadotrope cells.
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- 2022
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4. ODP335 Mutual Effects of Orexin and BMPs on Gonadotropin Expression by Mouse Gonadotrope LβT2 Cells
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Shinichi Hirata, Nanako Nakayama, Yoshiaki Soejima, Nahoko Iwata, Yasuhiro Nakano, Koichiro Yamamoto, Atsuhito Suyama, Takahiro Nada, Satoshi Fujisawa, and Fumio Otsuka
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Endocrinology, Diabetes and Metabolism - Abstract
Orexins are neuropeptides that express primarily in the hypothalamus and are produced in two isoforms, orexin A and orexin B. There are two kinds of G protein coupled receptors, orexin type 1 (OX1R) and type 2 (OX2R) receptors. Orexin has been reported to have key roles on sleep-wake regulation and feeding behavior in the central nervous system, whereas its receptors are also expressed in peripheral tissues including the endocrine organs, and orexin affects the regulation of the endocrine system. In our previous experiments, we have revealed the impact of orexins on anterior pituitary functions. For instance, we reported that orexin A plays an inhibitory role in prolactin production through the suppression of endogenous bone morphogenetic protein (BMP) activity in rat pituitary lactotrope GH3 cells. It was also reported that orexin A enhances pro-opiomelanocortin (POMC) transcription by upregulating corticotropin-releasing hormone (CRH) receptor signaling and by downregulating BMP-Smad signaling in mouse corticotope AtT20 cells. However, the effects of orexin on the endocrine function regarding gonadotrope cells remain unclear. We have recently uncovered that core clock genes and BMPs have mutual effects on luteinizing hormone (LH) expression in a phase-dependent manner by mouse gonadotrope LβT2 cells. In the present study, we investigated the effect of orexin on pituitary gonadotropin expression using LβT2 cells, which express OX1R and OX2R, by focusing on the functional involvement of BMP system and clock genes. It was revealed that orexin A stimulation increased LHβ and FSHβ mRNA expression in a concentration-responsive manner in the absence of GnRH, and interestingly, GnRH co-treatment further upregulated LHβ mRNA expression in LβT2 cells. Regarding the interrelationships between the signalings of orexin and BMPs, it was also revealed that orexin A pretreatment enhanced the BMP receptor signaling detected as the Smad1/5/9 phosphorylation, indicating that orexin enables to upregulate the BMP actions in LβT2 cells. In our previous studies, we reported that several BMP ligands such as BMP-6, -7 and 15 expressed in LβT2 cells can promote gonadotropin transcription, in which BMP-6 regulates GnRH-stimulated LH expression by modulating the sensitivity to somatostatin analogs. Based on the present results, it was implied that endogenous orexin can be functionally involved in the underlying mechanisms of gonadotropin expression. Collectively, orexin enhances gonadotropin expression by regulating BMP signaling in gonadotrope cells. Here, we will also discuss functional involvement of clock genes in the regulatory system of gonadotropin secretion induced by orexin and BMPs. Presentation: No date and time listed
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- 2022
5. ODP407 Effects of Leptin and Ghrelin on Ovarian Steroidogenesis and Involvement of BMP Action in Rat Granulosa Cells
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Yasuhiro Nakano, Chiaki Kashino, Toru Hasegawa, Nahoko Iwata, Yoshiaki Soejima, Atsuhito Suyama, Koichiro Yamamoto, and Fumio Otsuka
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Endocrinology, Diabetes and Metabolism - Abstract
Leptin and ghrelin are the two major hormones which regulate food intake and energy balance. They have also been reported to have pleiotropic functions, including the modulation of ovarian function via the hypothalamic-pituitary-ovarian system or in a direct manner to the ovaries. Blood leptin levels increase over the menstrual cycle and peak at the time of the luteinizing hormone (LH) surge. Leptin secreted from adipocytes acts on the hypothalamus and pituitary gland to stimulate the secretion of GnRH and gonadotropins. In the ovaries, high levels of leptin inhibit follicle-stimulating hormone (FSH)-induced steroid secretion and follicular development. Ghrelin, secreted by the stomach, has been reported to modulate GnRH secretion in the hypothalamus and to affect FSH and LH secretion, as well as steroidogenesis in the ovaries. Knockout of these hormones leads to impaired fertility. However, the mechanism of the direct effects of leptin and ghrelin on the ovaries has not been well elucidated. In the present study, we investigated the effects of leptin and ghrelin on the ovarian steroidogenesis using primary culture of rat granulosa cells, by focusing on the ovarian bone morphogenetic protein (BMP) system, which plays an important role in follicular development and steroidogenesis and acts as a luteinizing inhibitor. The results showed that treatment with leptin (1 to 300 ng/mL) did not affect either estradiol (E2) or progesterone (P4) production, but enhanced FSH-induced P4 production at low concentrations (10 ng/mL). On the other hand, treatment with ghrelin (1 to 300 nM) did not affect E2 and P4 production, but enhanced FSH-induced P4 production in a concentration-responsive manner. The mRNA levels of the follicular steroid synthases (StAR, P450scc, 3βHSD, 20αHSD) were examined. Leptin treatment enhanced 3βHSD mRNA levels. Both leptin treatment and ghrelin treatment decreased FSH-induced 20αHSD mRNA levels. However, both treatments decreased FSH-induced cAMP production. In addition, leptin treatment tended to suppress the transcriptional activity of Id-1 induced by BMP-6. Collectively, these results indicate that both leptin and ghrelin enhance FSH-induced P4 production by suppressing BMP signaling in rat granulosa cells. It was thus suggested that leptin and ghrelin which regulate food intake and energy balance can also act as endogenous regulators for the modulation of P4 synthesis and luteinizing process by ovarian follicles. Presentation: No date and time listed
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- 2022
6. Biphasic Roles of Clock Genes and Bone Morphogenetic Proteins in Gonadotropin Expression by Mouse Gonadotrope Cells
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Takahiro Nada, Yasuhiro Nakano, Fumio Otsuka, Yoshiaki Soejima, Atsuhito Suyama, Nahoko Iwata, and Koichiro Yamamoto
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endocrine system ,QH301-705.5 ,medicine.drug_class ,MAP Kinase Signaling System ,CLOCK Proteins ,Stimulation ,Gonadotrophs ,Gonadotropic cell ,Bone morphogenetic protein ,Catalysis ,Article ,Cell Line ,Inorganic Chemistry ,Gonadotropin-Releasing Hormone ,Mice ,Clock ,medicine ,Animals ,mitogen-activated protein kinase (MAPK) ,RNA, Messenger ,Biology (General) ,Physical and Theoretical Chemistry ,QD1-999 ,Molecular Biology ,Spectroscopy ,Chemistry ,bone morphogenetic protein (BMP) ,Organic Chemistry ,ARNTL Transcription Factors ,luteinizing hormone and mitogen-activated protein kinase (MAPK) ,General Medicine ,Period Circadian Proteins ,Luteinizing Hormone ,Computer Science Applications ,Gonadotropin secretion ,Cell biology ,CLOCK ,PER2 ,Cryptochromes ,Gene Expression Regulation ,Bone Morphogenetic Proteins ,Gonadotropin ,Mitogen-Activated Protein Kinases ,Luteinizing hormone ,hormones, hormone substitutes, and hormone antagonists ,gonadotropins - Abstract
Roles of Clock genes and the bone morphogenetic protein (BMP) system in the regulation of gonadotropin secretion by gonadotropin-releasing hormone (GnRH) were investigated using mouse gonadotropin L beta T2 cells. It was found that luteinizing hormone (LH)beta mRNA expression level in L beta T2 cells changed gradually over time, with LH beta expression being suppressed in the early phase up to 12 h and then elevated in the late phase 24 h after GnRH stimulation. In addition, the mRNA expression levels of Clock genes, including Bmal1, Clock, Per2, and Cry1, also showed temporal changes mimicking the pattern of LH beta expression in the presence and absence of GnRH. Notably, the expression levels of Bmal1 and Clock showed strong positive correlations with LH beta mRNA expression levels. Moreover, a functional link of the ERK signaling of mitogen-activated protein kinases (MAPKs) in the suppression of LH beta mRNA expression, as well as Bmal1 and Clock mRNA expression by GnRH at the early phase, was revealed. Inhibition of Bmal1 and Clock expression using siRNA was involved in the reduction in LH beta mRNA levels in the late phase 24 h after GnRH stimulation. Furthermore, in the presence of BMP-6 and -7, late-phase Bmal1 and LH beta mRNA expression after GnRH stimulation was significantly attenuated. Collectively, the results indicated that LH expression in gonadotrope cells exhibits Bmal1/Clock-dependent fluctuations under the influence of GnRH and that the fluctuations are regulated by ERK and BMPs in the early and late stages, respectively, in a phase-dependent manner after GnRH stimulation.
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- 2021
- Full Text
- View/download PDF
7. Interaction of ovarian steroidogenesis and clock gene expression modulated by bone morphogenetic protein-7 in human granulosa cells
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Nahoko Iwata, Takaaki Takiguchi, Tamami Aokage, Satoko Nagao, Fumio Otsuka, Toru Hasegawa, Takahiro Nada, Yoshiaki Soejima, Yuka Kozato, and Yasuhiro Nakano
- Subjects
endocrine system ,3-Hydroxysteroid Dehydrogenases ,Bone Morphogenetic Protein 7 ,Endocrinology, Diabetes and Metabolism ,CLOCK Proteins ,Gene Expression ,030209 endocrinology & metabolism ,Positive correlation ,03 medical and health sciences ,chemistry.chemical_compound ,Aromatase ,0302 clinical medicine ,Endocrinology ,Downregulation and upregulation ,Cell Line, Tumor ,Humans ,Progesterone ,Gene knockdown ,Messenger RNA ,Granulosa Cells ,Forskolin ,Estradiol ,Colforsin ,Cell biology ,PER2 ,Bone morphogenetic protein 7 ,CLOCK ,chemistry ,030220 oncology & carcinogenesis ,Female - Abstract
A functional link between clock gene expression and ovarian steroidogenesis was studied using human granulosa KGN cells. Similarities between changes in the mRNA and protein expression levels of Bmal1 and Clock and those of Per2 and Cry1 were found in KGN cells after treatment with forskolin. Among the interrelationships between the expression levels of clock and steroidogenic factors, Clock mRNA had a strongly positive correlation with P450arom and a negative correlation with 3βHSD. Knockdown of Clock gene by siRNA resulted in a significant reduction of estradiol production by inhibiting P450arom expression, while it induced a significant increase of progesterone production by upregulating 3βHSD in KGN cells treated with forskolin. Moreover, BMP-7 had an enhancing effect on the expression of Clock mRNA and protein in KGN cells. Thus, the expression levels of Clock, being upregulated by forskolin and BMP-7, were functionally linked to estradiol production and progesterone suppression by human granulosa cells.
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- 2019
8. Late-Onset Hypogonadism in a Male Patient with Long COVID Diagnosed by Exclusion of ME/CFS
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Yoshiaki Soejima, Yuki Otsuka, Kazuki Tokumasu, Yasuhiro Nakano, Ko Harada, Kenta Nakamoto, Naruhiko Sunada, Yasue Sakurada, Kou Hasegawa, Hideharu Hagiya, Keigo Ueda, and Fumio Otsuka
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free testosterone ,general fatigue ,General Medicine ,long COVID ,post-COVID condition ,late-onset hypogonadism - Abstract
After the acute phase of COVID-19, some patients have been reported to have persistent symptoms including general fatigue. We have established a COVID-19 aftercare clinic (CAC) to provide care for an increasing number of these patients. Here, we report the case of a 36-year-old man who developed post-COVID fatigue after acute infection with SARS-CoV-2. In the acute phase of COVID-19, the patient’s fever resolved within four days; however, general fatigue persisted for three months, and he visited our CAC 99 days after the initial infection. Examination revealed a high Aging Male’s Symptoms (AMS) score of 44 and low free testosterone (FT) level of 5.5 pg/mL, which meet the Japanese criteria of late-onset hypogonadism (LOH) syndrome. Imaging studies revealed an atrophic pituitary in addition to fatty liver and low bone mineral density. Anterior pituitary function tests showed a low follicle-stimulating hormonelevel and delayed reaction of luteinizing hormone (LH) after gonadotropin-releasing hormone (GnRH) stimulation, indicating the possibility of hypothalamic hypogonadism in addition to primary hypogonadism seen in patients with post-COVID-19 conditions. After the initiation of Japanese traditional medicine (Kampo medicine: hochuekkito followed by juzentaihoto), the patient’s symptoms as well as his AMS score and serum FT level were noticeably improved. Furthermore, follow-up tests of GnRH stimulation revealed improvements in LH responsiveness. Although many patients have been reported to meet the criteria of ME/CFS such as our case, we emphasize the possibility of other underlying pathologies including LOH syndrome. In conclusion, LOH syndrome should be considered a cause of general fatigue in patients with post-COVID-19 conditions and herbal treatment might be effective for long COVID symptoms due to LOH (264 words).
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- 2022
9. Involvement of clock gene expression, bone morphogenetic protein and activin in adrenocortical steroidogenesis by human H295R cells
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Koichiro Yamamoto, Fumio Otsuka, Nahoko Iwata, Yasuhiro Nakano, Takahiro Nada, Yoshiaki Soejima, Hiroko Ogawa, and Atsuhito Suyama
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endocrine system ,Endocrinology, Diabetes and Metabolism ,CLOCK Proteins ,Gene Expression ,030209 endocrinology & metabolism ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Endocrinology ,Cell Line, Tumor ,medicine ,Cytochrome P-450 CYP11B2 ,Humans ,Gene knockdown ,Messenger RNA ,Forskolin ,biology ,Adrenal cortex ,Colforsin ,Phosphoproteins ,Cell biology ,Activins ,CLOCK ,PER2 ,medicine.anatomical_structure ,chemistry ,Gene Expression Regulation ,030220 oncology & carcinogenesis ,HSD3B1 ,Bone Morphogenetic Proteins ,biology.protein ,Adrenal Cortex ,Follistatin - Abstract
Functional interactions between the levels of clock gene expression and adrenal steroidogenesis were studied in human adrenocortical H295R cells. Fluctuations of Bmal1, Clock, Per2 and Cry1 mRNA levels were found in H295R cells treated with forskolin (FSK) in a serum-free condition. The changes of clock gene expression levels were diverged, with Clock mRNA level being significantly higher than Cry1 and Per2 mRNA levels after 12-h stimulation with FSK. After FSK induction, mRNA levels of StAR and CYP11B2 were highest at 12 hours and CYP17 mRNA level reached a peak at 6 hours, but HSD3B1 mRNA level was transiently decreased at 3 hours. The expression levels of Clock mRNA showed a significant positive correlation with StAR among the interrelationships between mRNA levels of key steroidogenic factors and clock genes. Knockdown of Clock gene by siRNA led to a significant reduction of FSK-induced expression of StAR and CYP17 after 12-h treatment with FSK. BMP-6 and activin, which modulate adrenal steroidogenesis, had inhibitory effects on Clock mRNA expression, whereas treatment with follistatin, a binding protein of activin, increased Clock mRNA levels in the presence of FSK, suggesting an endogenous function of activin in regulation of Clock mRNA expression. Collectively, the results indicated that changes of Clock mRNA expression, being upregulated by FSK and suppressed by BMP-6 and activin, were tightly linked to StAR expression by human adrenocortical cells.
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- 2020
10. Involvement of NR5A1 and NR5A2 in the Regulation of Steroidogenesis by Clock Gene and BMPs by Human Granulosa Cells
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Fumio Otsuka, Yoshiaki Soejima, Yasuhiro Nakano, Koichiro Yamamoto, Atsuhito Suyama, Takahiro Nada, and Nahoko Iwata
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CLOCK ,endocrine system ,Ovary, Testes, and Impact of Hormones on Metabolic Function ,Text mining ,business.industry ,Endocrinology, Diabetes and Metabolism ,Liver receptor homolog-1 ,Reproductive Endocrinology ,Biology ,business ,AcademicSubjects/MED00250 ,Cell biology - Abstract
We previously reported that the expression levels of Clock gene are linked to the expression levels of steroidogenetic enzymes in human granulosa cells (EJ 2019). However, the downstream molecules of the Clock gene actions in the regulation of ovarian steroidogenesis have yet to be elucidated. In the present study, we investigated the roles of the transcription factors, NR5A1 (also known as SF-1) and NR5A2 (LRH-1), which play key roles in the reproductive function as well as steroidogenesis by focusing on the functional link between Clock gene and bone morphogenetic protein (BMP) signaling using human granulosa KGN cells. First of all, we examined the effects of BMPs/growth differentiation factor (GDF) on forskolin (FSK)-induced steroidogenesis. As a result, FSK-induced mRNA levels of StAR and P450scc, but not P450arom, were potently suppressed by treatments with BMP-6, -9, -15 and GDF-9. The expression levels of NR5A1 and NR5A2 mRNA were also upregulated by FSK treatment, while the BMP-target gene Id-1 mRNA levels were stimulated by the treatment with BMPs. Of interest, treatments with BMPs/GDF increased FSK-induced NR5A1 mRNA levels but suppressed FSK-induced NR5A2 mRNA levels by granulosa cells. The expression levels of NR5A1 mRNA were positively correlated with the changes of P450arom and 3βHSD mRNA, whereas the expression levels of NR5A2 mRNA were correlated with that of StAR and P450scc mRNA. In addition, the expression levels of NR5A1 and NR5A2 mRNAs were positively correlated with the levels of Clock mRNA. In particular, Clock mRNA levels showed highly positive correlation with the levels of NR5A2 mRNA compared with NR5A1 mRNA. Of note, Id-1 mRNA levels were positively correlated with the levels of NR5A1 mRNA, but negatively correlated with that of NR5A2 mRNA. Furthermore, the inhibition of Clock gene expression by siRNA attenuated the expression levels of NR5A1 and NR5A2 mRNA, resulting in decreased mRNA levels of StAR and P450arom in the presence of FSK. Thus, the present results suggested a novel mechanism by which Clock expression is functionally linked to the expression of NR5A1 and NR5A2, the latter of which is further regulated by BMP signaling by granulosa cells. The interaction among Clock, NR5A1/NR5A2 and BMPs may be involved in the fine tuning of steroidogenesis by ovarian follicles.
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- 2021
11. Aldosterone enhances progesterone biosynthesis regulated by bone morphogenetic protein in rat granulosa cells
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Toru Hasegawa, Takahiro Nada, Yoshiaki Soejima, Yasuhiro Nakano, Fumio Otsuka, Chiaki Kashino, Nahoko Iwata, Koichiro Yamamoto, and Atsuhito Suyama
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0301 basic medicine ,endocrine system ,medicine.medical_specialty ,Bone Morphogenetic Protein 6 ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,Bone morphogenetic protein ,Biochemistry ,Rats, Sprague-Dawley ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Endocrinology ,Mineralocorticoid receptor ,Internal medicine ,Follicular phase ,medicine ,Animals ,Receptor ,Aldosterone ,Molecular Biology ,Cells, Cultured ,Progesterone ,Granulosa Cells ,Cholesterol side-chain cleavage enzyme ,Cell Biology ,Polycystic ovary ,030104 developmental biology ,chemistry ,030220 oncology & carcinogenesis ,Molecular Medicine ,Phosphorylation ,Female ,Follicle Stimulating Hormone - Abstract
Aldosterone (Aldo) is involved in various cardiovascular diseases such as hypertension and heart failure. Aldo levels are known to be increased in patients with polycystic ovary syndrome, and expression of the mineralocorticoid receptor (MR) has also been detected in the ovary. However, the effect of Aldo on reproductive function has yet to be elucidated. Here, we examined the effects of Aldo on follicular steroidogenesis using primary culture of rat granulosa cells by focusing on the ovarian bone morphogenetic protein (BMP) system acting as a luteinizing inhibitor. We found that Aldo treatment increased FSH-induced progesterone production in a concentration-responsive manner. Consistent with the effects on steroidogenesis, Aldo increased mRNA levels of progesterogenic factor and enzymes including StAR and P450scc, whereas Aldo failed to change FSH-induced estradiol and cAMP synthesis or P450arom expression by granulosa cells. Progesterone production and StAR expression induced by FSH and Aldo were reversed by co-treatment with spironolactone, suggesting the involvement of geonomic MR action. Aldo treatment attenuated Smad1/5/9 phosphorylation and Id1 transcription induced by BMP-6. Furthermore, Aldo enhanced the expression of inhibitory Smad6 in the presence of BMP-6. In addition, BMP-6 downregulated MR expression, while Aldo modulated the mRNA levels of endogenous BMP-6 and BMP type-II receptors, indicating the existence of a feedback loop between the BMP system and MR in granulosa cells. Collectively, the results indicated that Aldo predominantly enhances FSH-induced progesterone production by inhibiting BMP-Smad signaling, suggesting a novel role of Aldo in ovarian steroidogenesis and a functional link between MR and BMP pathways in granulosa cells.
- Published
- 2020
12. Roles of NR5A1 and NR5A2 in the regulation of steroidogenesis by Clock gene and bone morphogenetic proteins by human granulosa cells
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Koichiro Yamamoto, Atsuhito Suyama, Takahiro Nada, Fumio Otsuka, Yoshiaki Soejima, Nahoko Iwata, and Yasuhiro Nakano
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endocrine system ,Endocrinology, Diabetes and Metabolism ,CLOCK Proteins ,Gene Expression ,Growth Differentiation Factor 9 ,Receptors, Cytoplasmic and Nuclear ,Ovary ,Bone morphogenetic protein ,Steroidogenic Factor 1 ,chemistry.chemical_compound ,Endocrinology ,medicine ,Humans ,Transcription factor ,Messenger RNA ,Forskolin ,Granulosa Cells ,Chemistry ,Cholesterol side-chain cleavage enzyme ,Liver receptor homolog-1 ,Cell biology ,CLOCK ,medicine.anatomical_structure ,embryonic structures ,Bone Morphogenetic Proteins ,Female ,Bone Morphogenetic Protein 15 ,Signal Transduction - Abstract
The functional role of the transcription factors NR5A1 and NR5A2 and their interaction with Clock gene and bone morphogenetic proteins (BMPs) were investigated in human granulosa KGN cells. Treatment with BMP-15 and GDF-9 suppressed forskolin (FSK)-induced steroidogenesis as shown by the mRNA expression levels of StAR and P450scc but not the mRNA expression level of P450arom. Of interest, treatment with BMP-15 and GDF-9 also suppressed FSK-induced NR5A2 mRNA expression. Treatment with BMP-15 suppressed NR5A2 mRNA and protein expression but increased Clock mRNA and protein expression levels by granulosa cells. The mRNA expression levels of NR5A1, but not those of NR5A2, were positively correlated with the levels of Clock mRNA, while the mRNA levels of Id-1, the target gene of BMP signaling, were positively correlated with those of NR5A1 but not with those of NR5A2. It was also demonstrated that the mRNA expression levels of NR5A1 were positively correlated with those of P450arom and 3βHSD, whereas the mRNA expression level of NR5A2 was correlated with those of StAR and P450scc. Furthermore, inhibition of Clock gene expression by siRNA attenuated the expression of NR5A1, and the mRNA levels of Clock gene were significantly correlated with those of NR5A1. Collectively, the results suggested a novel mechanism by which Clock gene expression induced by BMP-15 is functionally linked to the expression of NR5A1, whereas NR5A2 expression is suppressed by BMP-15 in granulosa cells. The interaction between Clock NR5A1/NR5A2 and BMP-15 is likely to be involved in the fine-tuning of steroidogenesis by ovarian granulosa cells.
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