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Human Adrenal Cortex affected by Primary Pigmented Nodular Adrenocortical Disease

ABSTRACT: Comparison between human adrenal cortex derived from adolescent female and human adrenal cortex derived from adolescent female affected by Primary Pigmented Nodular Adrenocortical Disease caused by germline mutation in PRKAR1a Keywords: other

ORGANISM(S): Homo sapiens

SUBMITTER: Anelia Horvath

PROVIDER: E-GEOD-2055 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Human Adrenal Cortex affected by Primary Pigmented Nodular Adrenocortical Disease

Project description:Comparison between human adrenal cortex derived from adolescent female and human adrenal cortex derived from adolescent female affected by Primary Pigmented Nodular Adrenocortical Disease caused by germline mutation in PRKAR1a Keywords: other

2005-03-11 | GSE2055 | GEO

Activation of cyclic AMP signaling leads to different pathway alterations in lesions of the adrenal cortex caused by germline PRKAR1A defects versus those due to somatic GNAS mutations

Project description:PRKAR1A inactivating mutations are responsible for primary pigmented nodular adrenocortical disease (PPNAD) whereas somatic GNAS activating mutations cause macronodular disease in the context of McCune-Albright syndrome (MAS), ACTH-independent hyperplasia (AIMAH) and, rarely, cortisol-producing adenomas (CPA). The whole-genome expression profile (WGEP) of normal (pooled) adrenals, PRKAR1A- (3) and GNAS-mutant (3) was studied. Total RNA obtained from adrenal tumors were compared to those samples obtained from normal adrenal pools

2011-11-15 | E-GEOD-33694 | biostudies-arrayexpress

Expression data from mouse adrenal glands extracted from wild-type and sf1:Cre; Prkar1a Fl/Fl (KO) adrenals

Project description:Prkar1a encodes one of the regulatory subunits of PKA. Prkar1a gene ablation in the adrenal cortex is associated with profound phenotypic alterations, constitutive PKA activation and reciprocal inhibition of WNT signallilng pathway We used microarrays to analyse gene expression in response to Prkar1a gene ablation Adrenal glands were dissected from KO (4) and wild-type littermate (4) mice

2016-02-06 | E-GEOD-77630 | biostudies-arrayexpress

Expression data from mouse adrenal glands extracted from wild-type and sf1:Cre; Prkar1a Fl/Fl (KO) adrenals

2016-02-06 | GSE77630 | GEO

Succinate mediates inflammation-induced adrenocortical dysfunction

Project description:Inflammation leads the hypothalamus-pituitary-adrenal (HPA) axis activation and increased production of glucocorticoids, which produced by the adrenal cortex, exert potent anti-inflammatory effects. The use of omics, including proteomics revealed metabolic changes in steroidogenic adrenocortical cells, including downregulation of the tricarboxylic acid (TCA) cycle and oxidative phosphorylation, decreased ATP production and induction of oxidative stress after lipopolysaccharide (LPS)-induced inflammation.

2023-07-21 | PXD036542 | Pride

MicroRNA signature of primary pigmented nodular adrenocortical disease: clinical correlations and regulation of Wnt signaling.

Project description:MicroRNAs comprise a novel group of gene regulators implicated in the development of different types of cancer; however, their role in primary pigmented nodular adrenocortical disease (PPNAD) has not been investigated. PPNAD is a bilateral adrenal hyperplasia often associated with Carney complex, a multiple neoplasia syndrome; both disorders are caused by protein kinase A (PKA) regulatory subunit type 1A (PRKARIA)-inactivating mutations. We identified a 44-microRNA gene signature of PPNAD after comparing PPNAD with normal adrenal samples. Specifically, 33 microRNAs were up-regulated and 11 down-regulated in PPNAD relative to normal tissues. These results were validated by stem loop real-time PCR analysis. Comparison of microRNA microarray data with clinicopathologic variables revealed a negative correlation (r = -0.9499) between let-7b expression and cortisol levels in patients with PPNAD. Integration of microRNA microarray with serial analysis of gene expression data together with bioinformatic algorithm predictions revealed nine microRNA-gene target pairs with a potential role in adrenal pathogenesis. Using a PPNAD cell line, we showed that miR-449 was up-regulated and identified its direct target, WNT1-inducible signaling pathway protein 2 (WISP2); in addition, pharmacologic inhibition of PKA resulted in the up-regulation of miR-449 leading to the suppression of WISP2. Overall, we investigated, for the first time, the microRNA profile and its clinical significance in PPNAD; these data also suggest that PKA, via microRNA regulation, affects the Wnt signaling pathway, which through expression and clinical studies is suspected to be a primary mediator of PRKAR1A-related tumorigenesis.

| S-EPMC3124768 | biostudies-literature

Expression data from mouse adrenal glands extracted from wild-type (WT) and Cyp11b2tm1.1(cre)Brlt;Prkar1afl/fl(KO) adrenals

Project description:We demonstrate that PKA signalling drives zonal conversion within adult adrenocortical lineage in a sexually dimorphic manner. Our data establish that Prkar1a genetic ablation (leading to constitutive PKA activation) in the adult adrenocortical lineage leads to endocrine hyperactivity and accelerates adrenal cortex renewal. This results in increased zona fasciculata differentiation and final conversion into reticularis-like zone. This phenomenon relies partly on sex-dependent mechanisms of cortical renewal, on which the male androgenic milieu exerts a repressive action through induction of WNT signalling, which in turn antagonizes PKA signalling and cortical cell turnover. We used microarrays to analyse gene expression in response to Prkar1a gene ablation in the adult adrenocortical cell lineage in both female and male mice and explored the effects of orchidectomy (GDX).

2017-09-16 | GSE103899 | GEO

Association of the M1V PRKAR1A mutation with primary pigmented nodular adrenocortical disease in two large families.

Project description:BackgroundCarney complex (CNC) is a familial multiple neoplasia syndrome frequently associated with primary pigmented nodular adrenocortical disease (PPNAD), a bilateral form of micronodular adrenal hyperplasia that leads to Cushing's syndrome (CS). Germline PRKAR1A mutations cause CNC and only rarely isolated PPNAD.Patients and methodsPRKAR1A mutation analysis in two large families with CS and no other CNC manifestations demonstrated a M1V germline mutation; a total of 21 asymptomatic individuals were screened, and mutation carriers were evaluated for CNC. The mutation was expressed in vitro and functionally tested for its effects on protein kinase A function.ResultsPresymptomatic testing identified five first-degree relatives who were M1V carriers and who were all diagnosed with subclinical, mild CS at ages ranging from 20-56 yr. There were no other signs of CNC. In a cell-free system, we detected a shorter compared with the wild-type type 1alpha regulatory subunit of protein kinase A (PRKAR1A) protein (43 kDa). This was not identified in cell lines from the patients or in transfection experiments in HEK293 cells that showed no detectable PRKAR1A protein from the M1V-bearing constructs. In these cells, the mutant mRNA was expressed in a 1:1 ratio.ConclusionIn two large families, the M1V PRKAR1A mutation resulted in a PPNAD-only phenotype with significant variability both in terms of age of onset and clinical severity. Expression studies showed a unique effect of this sequence change. This study has implications for genetic counseling of carriers of this PRKAR1A mutation and patients with CNC and PPNAD and for the study of PRKAR1A-related tumorigenesis.

| S-EPMC2805491 | biostudies-literature

mTOR pathway is activated by PKA in adrenocortical cells and participates in vivo to apoptosis resistance in primary pigmented nodular adrenocortical disease (PPNAD).

Project description:Primary pigmented nodular adrenocortical disease (PPNAD) is associated with inactivating mutations of the PRKAR1A tumor suppressor gene that encodes the regulatory subunit R1α of the cAMP-dependent protein kinase (PKA). In human and mouse adrenocortical cells, these mutations lead to increased PKA activity, which results in increased resistance to apoptosis that contributes to the tumorigenic process. We used in vitro and in vivo models to investigate the possibility of a crosstalk between PKA and mammalian target of rapamycin (mTOR) pathways in adrenocortical cells and its possible involvement in apoptosis resistance. Impact of PKA signaling on activation of the mTOR pathway and apoptosis was measured in a mouse model of PPNAD (AdKO mice), in human and mouse adrenocortical cell lines in response to pharmacological inhibitors and in PPNAD tissues by immunohistochemistry. AdKO mice showed increased mTOR complex 1 (mTORC1) pathway activity. Inhibition of mTORC1 by rapamycin restored sensitivity of adrenocortical cells to apoptosis in AdKO but not in wild-type mice. In both cell lines and mouse adrenals, rapid phosphorylation of mTORC1 targets including BAD proapoptotic protein was observed in response to PKA activation. Accordingly, BAD hyperphosphorylation, which inhibits its proapoptotic activity, was increased in both AdKO mouse adrenals and human PPNAD tissues. In conclusion, mTORC1 pathway is activated by PKA signaling in human and mouse adrenocortical cells, leading to increased cell survival, which is correlated with BAD hyperphosphorylation. These alterations could be causative of tumor formation.

| S-EPMC4184389 | biostudies-literature

Reconstitution of human adrenocortical specification and steroidogenesis using induced pluripotent stem cells [scRNA-seq]

Project description:The adrenal cortex produces vital steroid hormones that maintain homeostasis. While steroid hormones produced from the fetal zone adrenal cortex are essential for both fetal development and maintenance of pregnancy, the molecular mechanisms leading to human adrenal cortex development and steroid synthesis remain poorly understood due to the paucity of model systems. Through progressive generation of fetal zone adrenal cortex-like cells (FZLCs) from human induced pluripotent stem cells through posterior intermediate mesoderm-like, adrenogenic coelomic epithelium and adrenal primordium-like states, we provide the first in vitro reconstitution of human adrenocortical fetal specification. Generation of FZLCs faithfully recapitulates human embryonic adrenal cortex specification as evidenced by histomorphological and ultrastructural analysis, transcriptional profiles and delta-5 steroid biosynthesis and occurs in an adrenocorticotropic hormone (ACTH)-independent manner, consistent with clinical observations. Furthermore, we demonstrate that FZLC generation is promoted by SHH and inhibited by NOTCH, ACTIVIN and WNT signaling and that steroid synthesis is amplified by ACTH/PKA signaling and blocked by pharmacologic inhibitors of delta 5 steroid synthesis enzymes. Finally, NR5A1 appear to self-stabilize its promoter activity and promote FZLC survival and steroidogenesis. Together, these findings provide a framework for understanding and reconstituting human adrenocortical development in vitro and pave the way for future cell-based therapies of adrenal insufficiency.

2022-10-16 | GSE201794 | GEO

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