scholarly journals Transcriptomic analysis of gene cascades involved in protein kinase A and C signaling in the KGN line of human ovarian granulosa tumor cells†

2017 ◽  
Vol 96 (4) ◽  
pp. 855-865 ◽  
Author(s):  
Patricia G. Tremblay ◽  
Marc-André Sirard
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Tumor Cells ◽  
Transcriptomic Analysis ◽  
Kinase A

scholarly journals Role of Dosage-Sensitive Sex Reversal, Adrenal Hypoplasia Congenita, Critical Region on the X Chromosome, Gene 1 in Protein Kinase A- and Protein Kinase C-Mediated Regulation of the Steroidogenic Acute Regulatory Protein Expression in Mouse Leydig Tumor Cells: Mechanism of Action

Endocrinology ◽  
2008 ◽  
Vol 150 (1) ◽  
pp. 187-199 ◽  
Author(s):  
Pulak R. Manna ◽  
Matthew T. Dyson ◽  
Youngah Jo ◽  
Douglas M. Stocco
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Tumor Cells ◽  
Orphan Nuclear Receptor ◽  
Star Protein ◽  
Kinase C ◽  
Leydig Tumor Cells ◽  
Steroidogenic Acute Regulatory ◽  
Kinase A

Dosage-sensitive sex reversal, adrenal hypoplasia congenita, critical region on the X chromosome, gene 1 (DAX-1) is an orphan nuclear receptor that has been demonstrated to be instrumental to the expression of the steroidogenic acute regulatory (StAR) protein that regulates steroid biosynthesis in steroidogenic cells. However, its mechanism of action remains obscure. The present investigation was aimed at exploring the molecular involvement of DAX-1 in protein kinase A (PKA)- and protein kinase C (PKC)-mediated regulation of StAR expression and its concomitant impact on steroid synthesis using MA-10 mouse Leydig tumor cells. We demonstrate that activation of the PKA and PKC pathways, by a cAMP analog dibutyryl (Bu)2cAMP [(Bu)2cAMP] and phorbol 12-myristate 13-acetate (PMA), respectively, markedly decreased DAX-1 expression, an event that was inversely correlated with StAR protein, StAR mRNA, and progesterone levels. Notably, the suppression of DAX-1 requires de novo transcription and translation, suggesting that the effect of DAX-1 in regulating StAR expression is dynamic. Chromatin immunoprecipitation studies revealed the association of DAX-1 with the proximal but not the distal region of the StAR promoter, and both (Bu)2cAMP and PMA decreased in vivo DAX-1-DNA interactions. EMSA and reporter gene analyses demonstrated the functional integrity of this interaction by showing that DAX-1 binds to a DNA hairpin at position −44/−20 bp of the mouse StAR promoter and that the binding of DAX-1 to this region decreases progesterone synthesis by impairing transcription of the StAR gene. In support of this, targeted silencing of endogenous DAX-1 elevated basal, (Bu)2cAMP-, and PMA-stimulated StAR expression and progesterone synthesis. Transrepression of the StAR gene by DAX-1 was tightly associated with expression of the nuclear receptors Nur77 and steroidogenic factor-1, demonstrating these factors negatively modulate the steroidogenic response. These findings provide insight into the molecular events by which DAX-1 influences the PKA and PKC signaling pathways involved in the regulation of the StAR protein and steroidogenesis in mouse Leydig tumor cells. The characterization of protein kinase A- and protein kinase C-mediated steroidogenic acute regulatory (StAR) expression and steroidogenesis suggests that the orphan nuclear receptor DAX-1 is an important regulator of the steroidogenic response in Leydig cells.

scholarly journals Mutation of Prkar1a Causes Osteoblast Neoplasia Driven by Dysregulation of Protein Kinase A

2008 ◽  
Vol 22 (2) ◽  
pp. 430-440 ◽  
Author(s):  
Emilia Pavel ◽  
Kiran Nadella ◽  
William H. Towns ◽  
Lawrence S. Lawrence S.
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Tumor Cells ◽  
Bone Tumors ◽  
Skin Pigmentation ◽  
Primary Cultures ◽  
Genetic Defect ◽  
Wnt Signaling Pathway ◽  
Endocrine Tumors ◽  
Kinase A

Abstract Carney complex (CNC) is an autosomal dominant neoplasia syndrome caused by inactivating mutations in PRKAR1A, the gene encoding the type 1A regulatory subunit of protein kinase A (PKA). This genetic defect induces skin pigmentation, endocrine tumors, myxomas, and schwannomas. Some patients with the complex also develop myxoid bone tumors termed osteochondromyxomas. To study the link between the PRKAR1A mutations and tumor formation, we generated a mouse model of this condition. Prkar1a+/− mice develop bone tumors with high frequency, although these lesions have not yet been characterized, either from human patients or from mice. Bone tumors from Prkar1a+/− mice were heterogeneous, including elements of myxomatous, cartilaginous, and bony differentiation that effaced the normal bone architecture. Immunohistochemical analysis identified an osteoblastic origin for the abnormal cells associated with islands of bone. To better understand these cells at the biochemical level, we isolated primary cultures of tumoral bone and compared them with cultures of bone from wild-type animals. The tumor cells exhibited the expected decrease in Prkar1a protein and exhibited increased PKA activity. At the phenotypic level, we observed that tumor cells behaved as incompletely differentiated osteoblasts and were able to form tumors in immunocompromised mice. Examination of gene expression revealed down-regulation of markers of bone differentiation and increased expression of locally acting growth factors, including members of the Wnt signaling pathway. Tumor cells exhibited enhanced growth in response to PKA-stimulating agents, suggesting that tumorigenesis in osteoblast precursor cells is driven by effects directly mediated by the dysregulation of PKA.

scholarly journals Geranylgeraniol enhances testosterone production via the cAMP/protein kinase A pathway in testis-derived I-10 tumor cells

2016 ◽  
Vol 80 (4) ◽  
pp. 791-797 ◽  
Author(s):  
Hsin-Jung Ho ◽  
Hitoshi Shirakawa ◽  
Risa Yoshida ◽  
Asagi Ito ◽  
Misato Maeda ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Tumor Cells ◽  
Testosterone Production ◽  
Kinase A

scholarly journals Cysteine Sulfoxides Enhance Steroid Hormone Production via Activation of the Protein Kinase A Pathway in Testis-Derived I-10 Tumor Cells

Molecules ◽  
2020 ◽  
Vol 25 (20) ◽  
pp. 4694
Author(s):  
Yuya Nakayama ◽  
Hsin-Jung Ho ◽  
Miki Yamagishi ◽  
Hiroyuki Ikemoto ◽  
Michio Komai ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Tumor Cells ◽  
Steroid Hormone ◽  
Hormone Production ◽  
Onion Extract ◽  
Testosterone Levels ◽  
Age Related ◽  
Cysteine Sulfoxides ◽  
Kinase A

Testosterone plays an important role in male sexual characteristics and maturation, and decreased testosterone levels increase the risk of several diseases. Recently, onion extract rich in cysteine sulfoxides, which are amino acids unique to onions, has been reported to alleviate age-related symptoms resulting from decreased testosterone levels in males. However, the mechanism underlying the suppression of low testosterone levels by cysteine sulfoxides has not been elucidated. In this study, we found that onion extract containing cysteine sulfoxides enhanced progesterone, a precursor of testosterone, in mouse testis-derived I-10 tumor cells. Furthermore, cysteine sulfoxides activated protein kinase A (PKA) and cyclic adenosine monophosphate response element-binding protein, which are key factors in steroidogenesis. These results suggest that cysteine sulfoxides enhance steroid hormone production via activation of the PKA signaling pathway.

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