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 Haploinsufficiency at the Protein Kinase A RIα Gene Locus Leads to Fertility Defects in Male Mice and Men

2006 ◽  
Vol 20 (10) ◽  
pp. 2504-2513 ◽  
Author(s):  
Kimberly A. Burton ◽  
Deborah A. McDermott ◽  
David Wilkes ◽  
Melissa N. Poulsen ◽  
Michael A. Nolan ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Germ Cells ◽  
Skin Pigmentation ◽  
Structural Defects ◽  
Regulatory Subunit ◽  
Endocrine Tumors ◽  
Male Mice ◽  
Inactivating Mutations ◽  
Kinase A

Abstract Carney complex (CNC) is a familial multiple neoplasia syndrome characterized by spotty skin pigmentation, cardiac and cutaneous myxomas, and endocrine tumors. CNC is inherited as an autosomal dominant trait and is transmitted with greater frequency by women vs. men. Nearly two thirds of CNC patients are heterozygous for inactivating mutations in the gene encoding the protein kinase A (PKA) type Iα regulatory subunit (RIα), PRKAR1. We report here that male mice heterozygous for the Prkar1a gene have severely reduced fertility. Sperm from Prkar1a heterozygous mice are morphologically abnormal and reduced in number. Genetic rescue experiments reveal that this phenotype results from elevated PKA catalytic activity in germ cells as early as the pachytene stage of spermatogenesis. Consistent with this defect in the male mutant mice, sperm from CNC patients heterozygous for PRKAR1A mutations were also found to be morphologically aberrant and decreased in number. We conclude that unregulated PKA activity in male meiotic or postmeiotic germ cells leads to structural defects in mature sperm and results in reduced fertility in mice and humans, contributing to the strikingly reduced transmission of PRKAR1A inactivating mutations by male patients with CNC.

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.

Protein Kinase A Alterations in Endocrine Tumors

2012 ◽  
Vol 44 (10) ◽  
pp. 741-748 ◽  
Author(s):  
B. Yu ◽  
B. Ragazzon ◽  
M. Rizk-Rabin ◽  
J. Bertherat
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Endocrine Tumors ◽  
Kinase A

Protein kinase A and its role in human neoplasia: the Carney complex paradigm.

2004 ◽  
Vol 11 (2) ◽  
pp. 265-280 ◽  
Author(s):  
I Bossis ◽  
A Voutetakis ◽  
T Bei ◽  
F Sandrini ◽  
K J Griffin ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Cushing Syndrome ◽  
Skin Pigmentation ◽  
Suppressor Gene ◽  
Carney Complex ◽  
Regulatory Subunit ◽  
Extensive Literature ◽  
Bilateral Adrenal Hyperplasia ◽  
Kinase A

The type 1 alpha regulatory subunit (R1alpha) of cAMP-dependent protein kinase A (PKA) (PRKAR1A) is an important regulator of the serine-threonine kinase activity catalyzed by the PKA holoenzyme. Carney complex (CNC) describes the association 'of spotty skin pigmentation, myxomas, and endocrine overactivity'; CNC is in essence the latest form of multiple endocrine neoplasia to be described and affects the pituitary, thyroid, adrenal and gonadal glands. Primary pigmented nodular adrenocortical disease (PPNAD), a micronodular form of bilateral adrenal hyperplasia that causes a unique, inherited form of Cushing syndrome, is also the most common endocrine manifestation of CNC. CNC and PPNAD are genetically heterogeneous but one of the responsible genes is PRKAR1A, at least for those families that map to 17q22-24 (the chromosomal region that harbors PRKAR1A). CNC and/or PPNAD are the first human diseases to be caused by mutations in one of the subunits of the PKA holoenzyme. Despite the extensive literature on R1alpha and PKA, little is known about their potential involvement in cell cycle regulation, growth and/or proliferation. The presence of inactivating germline mutations and the loss of its wild-type allele in CNC lesions indicated that PRKAR1A could function as a tumor-suppressor gene in these tissues. However, there are conflicting data in the literature about PRKAR1A's role in human neoplasms, cancer cell lines and animal models. In this report, we review briefly the genetics of CNC and focus on the involvement of PRKAR1A in human tumorigenesis in an effort to reconcile the often diametrically opposite reports on R1alpha.

scholarly journals The Lutropin/Choriogonadotropin Receptor-Induced Phosphorylation of the Extracellular Signal-Regulated Kinases in Leydig Cells Is Mediated by a Protein Kinase A-Dependent Activation of Ras

2003 ◽  
Vol 17 (11) ◽  
pp. 2189-2200 ◽  
Author(s):  
Takashi Hirakawa ◽  
Mario Ascoli
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Leydig Cells ◽  
Primary Cultures ◽  
Nucleotide Exchange ◽  
Camp Phosphodiesterase ◽  
Human Choriogonadotropin ◽  
Extracellular Signal ◽  
Guanosine Triphosphatase ◽  
Kinase A

Abstract The pathways involved in activation of the ERK1/2 cascade in Leydig cells were examined in MA-10 cells expressing the recombinant human LH receptor (hLHR) and in primary cultures of rat Leydig cell precursors. In MA-10 cells expressing the recombinant hLHR, human choriogonadotropin-induced activation of ERK1/2 is effectively inhibited by overexpression of a cAMP phosphodiesterase (a manipulation that blunts the human choriogonadotropin-induced cAMP response), by addition of H89 (a selective inhibitor of protein kinase A), or by overexpression of the heat-stable protein kinase A inhibitor, but not by overexpression of an inactive mutant of this inhibitor. Stimulation of hLHR did not activate Rap1, but activated Ras in an H89-sensitive fashion. Addition of H89 to MA-10 cells that had been cotransfected with a guanosine triphosphatase-deficient mutant of Ras almost completely inhibited the hLHR-mediated activation of ERK1/2. We also show that 8-bromo-cAMP activates Ras and ERK1/2 in MA-10 cells and in primary cultures of rat Leydig cells precursors in an H89-sensitive fashion, whereas a cAMP analog 8-(4-chloro-phenylthio)-2′-O-methyl-cAMP (8CPT-2Me-cAMP) that is selective for cAMP-dependent guanine nucleotide exchange factor has no effect. Collectively, our results show that the hLHR-induced phosphorylation of ERK1/2 in Leydig cells is mediated by a protein kinase A-dependent activation of Ras.

scholarly journals Estradiol Modulates Translocator Protein (TSPO) and Steroid Acute Regulatory Protein (StAR) via Protein Kinase A (PKA) Signaling in Hypothalamic Astrocytes

Endocrinology ◽  
2014 ◽  
Vol 155 (8) ◽  
pp. 2976-2985 ◽  
Author(s):  
Claire Chen ◽  
John Kuo ◽  
Angela Wong ◽  
Paul Micevych
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Primary Cultures ◽  
Regulatory Protein ◽  
Estrogen Receptor Α ◽  
Translocator Protein ◽  
Calcium Stores ◽  
Female Rat ◽  
Transporter Protein ◽  
Kinase A

The ability of the central nervous system to synthesize steroid hormones has wide-ranging implications for physiology and pathology. Among the proposed roles of neurosteroids is the regulation of the LH surge. This involvement in the estrogen-positive feedback demonstrates the integration of peripheral steroids with neurosteroids. Within the female hypothalamus, estradiol from developing follicles stimulates progesterone synthesis in astrocytes, which activate neural circuits regulating gonadotropin (GnRH) neurons. Estradiol acts at membrane estrogen receptor-α to activate cellular signaling that results in the release of inositol trisphosphate-sensitive calcium stores that are sufficient to induce neuroprogesterone synthesis. The purpose of the present studies was to characterize the estradiol-induced signaling leading to activation of steroid acute regulatory protein (StAR) and transporter protein (TSPO), which mediate the rate-limiting step in steroidogenesis, ie, the transport of cholesterol into the mitochondrion. Treatment of primary cultures of adult female rat hypothalamic astrocytes with estradiol induced a cascade of phosphorylation that resulted in the activation of a calcium-dependent adenylyl cyclase, AC1, elevation of cAMP, and activation of both StAR and TSPO. Blocking protein kinase A activation with H-89 abrogated the estradiol-induced neuroprogesterone synthesis. Thus, together with previous results, these experiments completed the characterization of how estradiol action at the membrane leads to the augmentation of neuroprogesterone synthesis through increasing cAMP, activation of protein kinase A, and the phosphorylation of TSPO and StAR in hypothalamic astrocytes.

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
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