Activins regulate 17β-hydroxysteroid dehydrogenase type I transcription in murine gonadotrope cells

Bąk, Beata; Carpio, Laura; Kipp, Jinjing L; Lamba, Pankaj; Wang, Ying; Ge, Ren‐Shan; Hardy, Matthew P; Mayo, Kelly E.; Bernard, Daniel J.

doi:10.1677/joe-08-0460

Cited by 9 publications

(4 citation statements)

References 51 publications

(59 reference statements)

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“…Only a few genes were previously known to be associated with activin A signaling. For instance, activin A regulates transcription of sex hormone synthesizing enzymes of the hydroxysteroid dehydrogenase (Hsd17) family . Link et al uncovered that prostate transmembrane protein, androgen induced 1 ( Pmepa1 ) is a novel and direct target gene of activin A‐mediated Smad2/3 signaling in the brain.…”

Section: Discussionmentioning

confidence: 99%

“…For instance, activin A regulates transcription of sex hormone synthesizing enzymes of the hydroxysteroid dehydrogenase (Hsd17) family. (28) Link et al (29) uncovered that prostate transmembrane protein, androgen induced 1 (Pmepa1) is a novel and direct target gene of activin A-mediated Smad2/3 signaling in the brain. Moreover, we found that activin A regulates expression of genes that are known to be involved in TGF-b signaling.…”

Section: Discussionmentioning

confidence: 99%

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Activin A is a prominent autocrine regulator of hepatocyte growth arrest

Haridoss

Yovchev

Schweizer

et al. 2017

Hepatology Communications

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Activin A, a multifunctional cytokine, plays an important role in hepatocyte growth suppression and is involved in liver size control. The present study was aimed to determine the cell location of activin A in the normal rat liver microenvironment and the contribution of activin A signaling to the hepatocyte phenotype to obtain insight into molecular mechanisms. Immunohistochemical and in situ hybridization analyses identified hepatocytes as the major activin A‐positive cell population in normal liver and identified mast cells as an additional activin A source. To investigate paracrine and autocrine activin A‐stimulated effects, hepatocytes were cocultured with engineered activin A‐secreting cell lines (RF1, TL8) or transduced with an adeno‐associated virus vector encoding activin βA, which led to strikingly altered expression of cell cycle‐related genes (Ki‐67, E2F transcription factor 1 [E2F1], minichromosome maintenance complex component 2 [Mcm2], forkhead box M1 [FoxM1]) and senescence‐related genes (cyclin‐dependent kinase inhibitor 2B [p15INK4b/CDKN2B], differentiated embryo‐chondrocyte expressed gene 1 [DEC1]) and reduced proliferation and induction of senescence. Microarray analyses identified 453 differentially expressed genes, many of which were not yet recognized as activin A downstream targets (e.g., ADAM metallopeptidase domain 12 [Adam12], semaphorin 7A [Sema7a], LIM and cysteine‐rich domains‐1 [Lmcd1], DAB2, clathrin adaptor protein [Dab2]). Among the main activin A‐mediated molecular/cellular functions are cellular growth/proliferation and movement, molecular transport, and metabolic processes containing highly down‐regulated genes, such as cytochrome P450, subfamily 2, polypeptide 11 (Cyp2C11), sulfotransferase family 1A, member 1 (Sult1a1), glycine‐N‐acyltransferase (Glyat), and bile acid‐CoA:amino acid N‐acyltransferase (Baat). Moreover, Ingenuity Pathway Analyses identified particular gene networks regulated by hepatocyte nuclear factor (HNF)‐4α and peroxisome proliferator‐activated receptor gamma (PPARγ) as key targets of activin A signaling. Conclusion: Our in vitro models demonstrated that activin A‐stimulated growth inhibition and cellular senescence is mediated through p15INK4b/CDKN2B and is associated with up‐ and down‐regulation of numerous target genes involved in multiple biological processes performed by hepatocytes, suggesting that activin A fulfills a critical role in normal liver function. (Hepatology Communications 2017;1:852‐870)

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Activin A is a prominent autocrine regulator of hepatocyte growth arrest

Haridoss

Yovchev

Schweizer

et al. 2017

Hepatology Communications

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“…In mouse GCs, the lipotoxicity, which is closely related to obesity, significantly decreases the mRNA expression of HSD17B1 (Hua et al., 2020), and it is suggested that Farnesoid X receptor regulates the mRNA expression of HSD17B1 and thus regulates the synthesis of steroid hormone (Takae et al., 2019). In murine gonadotrope cells, HSD17B1 has been suggested as an activin‐responsive gene (Bak et al., 2009). Moreover, the methoxychlor is a known endocrine disruptor that affects adult rodent females by causing reduced fertility, and Basavarajappa et al have found that the methoxychlor decreases the sex steroid hormone levels by inhibiting the expression of HSD17B1 in mouse (Basavarajappa et al., 2011).…”

Section: Discussionmentioning

confidence: 99%

FoxA2 and p53 regulate the transcription of HSD17B1 in ovarian granulosa cells of pigs

Yuan

Zhou

Qiao

et al. 2020

Reprod Domestic Animals

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The oestrogens have been highly implicated in the fertility of female animals. It is widely known that the oestrogens are primarily synthetized by the ovarian granulosa cells (GCs), and the final and essential step of this process is to catalyse the oestrone to the more active oestradiol by the protein coded by hydroxysteroid 17‐beta dehydrogenase 1 (HSD17B1) gene. However, the molecular mechanism regarding the transcription of HSD17B1 remains to be fully elucidated in ovarian GCs. In this study, the 5’‐deletion, luciferase assay and chromatin immunoprecipitation (ChIP) were utilized to explore the molecular regulation of transcription of HSD17B1 with the porcine ovarian GCs as the cellular model. After the deletions with −2105 to −1754 bp, −1753 to −1429 bp, −1430 to −1081 bp and −1082 to −730 bp, the relative luciferase activity of HSD17B1 promoter did not change significantly, but the deletion of −731 to −332 bp significantly increased the relative luciferase activity of HSD17B1 promoter, and an insertion (GTTT) that might raise the transcription of HSD17B1 was identified at −401 bp of HSD17B1. These findings suggested the region from −731 to +38 bp was the core promoter of HSD17B1, and the region between −731 to −332 bp might be a silence element for HSD17B1. Furthermore, the forkhead box A2 (FoxA2) directly bound at −412 to −401 bp to negatively but p53 bound at −383 to −374 bp to positively regulate the transcription and translation of HSD17B1 in ovarian GCs. These findings will improve our understanding on HSD17B1‐mediated oestrogens and provide useful information for further investigations into fertility of females.

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“…The results did not indicate, however, whether these effects were gene specific or reflected a generalized antagonism of activinlike signaling. We therefore examined the effects of TSA on a second activin A-responsive gene in LβT2 cells, 17β-hydroxysteroid dehydrogenase type I (Hsd17b1) (Bak et al 2009). Similar to the case with Fshb, TSA greatly attenuated basal and activin A-induced Hsd17b1 expression ( Fig.…”

Section: Tsa Impairs Expression Of Another Activin Target Hsd17b1mentioning

confidence: 99%

HDAC inhibitors impair Fshb subunit expression in murine gonadotrope cells

Schang

Toufaily

Bernard

2019

Journal of Molecular Endocrinology

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Fertility is dependent on follicle-stimulating hormone (FSH), a product of gonadotrope cells of the anterior pituitary gland. Hypothalamic gonadotropin-releasing hormone (GnRH) and intra-pituitary activins are regarded as the primary drivers of FSH synthesis and secretion. Both stimulate expression of the FSH beta subunit gene (Fshb), although the underlying mechanisms of GnRH action are poorly described relative to those of the activins. There is currently no consensus on how GnRH regulates Fshb transcription, as results vary across species and between in vivo and in vitro approaches. One of the more fully developed models suggests that the murine Fshb promoter is tonically repressed by histone deacetylases (HDACs) and that GnRH relieves this repression, at least in immortalized murine gonadotrope-like cells (LβT2 and αT3-1). In contrast, we observed that the class I/II HDAC inhibitor trichostatin A (TSA) robustly inhibited basal, activin A-, and GnRH-induced Fshb mRNA expression in LβT2 cells and in primary murine pituitary cultures. Similar results were obtained with the class I specific HDAC inhibitor, entinostat, whereas two class II-specific inhibitors, MC1568 and TMP269, had no effects on Fshb expression. Collectively, these data suggest that class I HDACs are positive, not negative, regulators of Fshb expression in vitro and that, contrary to earlier reports, GnRH may not stimulate Fshb by inhibiting HDAC-mediated repression of the gene.

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Activins regulate 17β-hydroxysteroid dehydrogenase type I transcription in murine gonadotrope cells

Cited by 9 publications

References 51 publications

Activin A is a prominent autocrine regulator of hepatocyte growth arrest

Activin A is a prominent autocrine regulator of hepatocyte growth arrest

FoxA2 and p53 regulate the transcription of HSD17B1 in ovarian granulosa cells of pigs

HDAC inhibitors impair Fshb subunit expression in murine gonadotrope cells

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