Steroidogenesis and extracellular cAMP accumulation in adrenal tumor cell cultures

Schimmer, Bernard P.; Zimmerman, Arthur E.

doi:10.1016/0303-7207(76)90060-5

Cited by 33 publications

(5 citation statements)

References 19 publications

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“…Cells were stimulated with 20 nm ACTH, and effects were measured after a 24-h stimulation. This concentration of ACTH maximally activates cAMP and MAPK signaling (27,28) and produces maximum effects on steroidogenesis (28), proliferation (29), and Odc1 induction (30); the 24-h time period was chosen because the hormone is known to have a delayed inductive effect on most genes involved in steroidogenesis and because much of the work published previously has used similar time points of induction (e.g. Ref.…”

Section: Discussionmentioning

confidence: 99%

Global Profiles of Gene Expression Induced by Adrenocorticotropin in Y1 Mouse Adrenal Cells

et al. 2006

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ACTH regulates the steroidogenic capacity, size, and structural integrity of the adrenal cortex through a series of actions involving changes in gene expression; however, only a limited number of ACTH-regulated genes have been identified, and these only partly account for the global effects of ACTH on the adrenal cortex. In this study, a National Institute on Aging 15K mouse cDNA microarray was used to identify genome-wide changes in gene expression after treatment of Y1 mouse adrenocortical cells with ACTH. ACTH affected the levels of 1275 annotated transcripts, of which 46% were up-regulated. The up-regulated transcripts were enriched for functions associated with steroid biosynthesis and metabolism; the down- regulated transcripts were enriched for functions associated with cell proliferation, nuclear transport and RNA processing, including alternative splicing. A total of 133 different transcripts, i.e. only 10% of the ACTH-affected transcripts, were represented in the categories above; most of these had not been described as ACTH-regulated previously. The contributions of protein kinase A and protein kinase C to these genome-wide effects of ACTH were evaluated in microarray experiments after treatment of Y1 cells and derivative protein kinase A-defective mutants with pharmacological probes of each pathway. Protein kinase A-dependent signaling accounted for 56% of the ACTH effect; protein kinase C-dependent signaling accounted for an additional 6%. These results indicate that ACTH affects the expression profile of Y1 adrenal cells principally through cAMP- and protein kinase A- dependent signaling. The large number of transcripts affected by ACTH anticipates a broader range of actions than previously appreciated.

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Section: Discussionmentioning

confidence: 99%

Global Profiles of Gene Expression Induced by Adrenocorticotropin in Y1 Mouse Adrenal Cells

et al. 2006

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“…The concentrations of ACTH that effectively stimulated MAP kinase activity were 50-fold lower than the concentrations of hormone required to produce detectable changes in cAMP levels in these cells (28), raising the possibility that ACTH exerted its effects on MAP kinase via a cAMP-independent pathway. To test this hypothesis, we examined the ability of ACTH to stimulate MAP kinase phosphorylation in the cAMP-resistant, PKA-defective mutant Kin-8.…”

Section: Regulation Of the Map Kinase Pathwaymentioning

confidence: 95%

Unmasking a Growth-promoting Effect of the Adrenocorticotropic Hormone in Y1 Mouse Adrenocortical Tumor Cells

Lotfi

Todorović

Armelin

et al. 1997

Journal of Biological Chemistry

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The growth-inhibitory effects of the adrenocorticotropic hormone (ACTH) 1 on adrenal cells in vitro are well documented. ACTH-induced inhibition of cell proliferation has been observed in the Y1 mouse adrenocortical tumor cell line (1) as well as in normal adrenocortical cells isolated from a variety of species including rat, cow, and human (for review, see Ref.2). ACTH arrests dividing adrenal cells by interfering with progression through the G 1 phase of the cell cycle (3) and inhibits the initiation of DNA synthesis in G 1 -arrested cells following addition of serum or growth factors (4, 5). Several lines of evidence indicate that the growth-inhibitory effect of ACTH is mediated by cAMP with the most compelling data arising from studies of Y1 adrenal tumor cells harboring dominant inhibitory mutations in cAMP-dependent protein kinase (PKA) that specifically disrupt cAMP-dependent signaling pathways (6). These PKA mutants are resistant to the growth-inhibitory actions of ACTH and cAMP analogs (7,8), indicating that cAMP and PKA are obligatory components of this effect of ACTH on cell proliferation. The inhibition of proliferation seen in isolated adrenocortical cells contrasts sharply with the growth-promoting effects of ACTH on the adrenal gland in vivo and has led to the widely held view that ACTH serves as an indirect mitogen for the adrenal cortex in intact animals (2). Paradoxically, however, ACTH induces expression of genes often associated with enhanced cell proliferation such as ornithine decarboxylase (9) and fos and jun protooncogenes (10 -12) in isolated adrenocortical cells, raising the possibility of an underlying growth-promoting action of the hormone.The MAP kinase cascade, an important regulator of cell cycle progression, has been used recently as a biochemical marker to evaluate the status of hormones and growth factors as mitogens. Activation of the MAP kinase pathway is involved in the mitogenic effects of growth factors such as epidermal growth factor, platelet-derived growth factor, and FGF (13, 14), acting via receptor tyrosine kinases and also appears to mediate the mitogenic effects of thyrotropin on thyrocytes (15), angiotensin II on smooth muscle cells (16), and thrombin on fibroblasts (17), each acting through a G protein-coupled receptor. Conversely, inhibition of the MAP kinase cascade accompanies the growthinhibitory effects of cAMP observed in fibroblasts and other cell types (for review, see Ref. 18). In the present study, we examined the regulation of the MAP kinase pathway in Y1 mouse adrenocortical tumor cells to reconcile the growth-inhibiting effect of ACTH in vitro with the conflicting biochemical data that suggests an underlying mitogenic effect of the hormone. Although we expected that ACTH would inhibit MAP kinase activity in Y1 cells, consistent with the growth-inhibitory effects of the hormone, we find that ACTH activates the MAP kinase cascade via a signaling mechanism that is cAMP-independent. This effect of ACTH on MAP kinase prompted us to reexamine the effects of...

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“…For example, the β-adrenoceptor agonist isoproterenol stimulates cAMP secretion from rat cultured glioma cells ( Doore et al, 1975 ) and turkey erythrocytes ( Rindler et al, 1978 ). In mouse adrenocortical tumor cell line, the intracellular cAMP formed in response to ACTH appeared extracellularly in few minutes ( Schimmer and Zimmerman, 1976 ). In healthy volunteers, infusion of glucagon after hepatic venous catheterization was associated with a marked increase in both the splanchnic cAMP production and in the arterial cyclic nucleotide levels ( Grill et al, 1979 ).…”

Section: Activation Of Gspcr and The Extracellular Camp-adenosine Patmentioning

confidence: 99%

New perspectives in signaling mediated by receptors coupled to stimulatory G protein: the emerging significance of cAMP eï¬„ux and extracellular cAMP-adenosine pathway

2015

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G protein-coupled receptors (GPCRs) linked to stimulatory G (Gs) proteins (GsPCRs) mediate increases in intracellular cyclic AMP as consequence of activation of nine adenylyl cyclases , which differ considerably in their cellular distribution and activation mechanisms. Once produced, cyclic AMP may act via distinct intracellular signaling effectors such as protein kinase A and the exchange proteins activated by cAMP (Epacs). More recently, attention has been focused on the eﬄux of cAMP through a specific transport system named multidrug resistance proteins that belongs to the ATP-binding cassette transporter superfamily. Outside the cell, cAMP is metabolized into adenosine, which is able to activate four distinct subtypes of adenosine receptors, members of the GPCR family: A1, A2A, A2B, and A3. Taking into account that this phenomenon occurs in numerous cell types, as consequence of GsPCR activation and increment in intracellular cAMP levels, in this review, we will discuss the impact of cAMP eﬄux and the extracellular cAMP-adenosine pathway on the regulation of GsPCR-induced cell response.

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Steroidogenesis and extracellular cAMP accumulation in adrenal tumor cell cultures

Cited by 33 publications

References 19 publications

Global Profiles of Gene Expression Induced by Adrenocorticotropin in Y1 Mouse Adrenal Cells

Global Profiles of Gene Expression Induced by Adrenocorticotropin in Y1 Mouse Adrenal Cells

Unmasking a Growth-promoting Effect of the Adrenocorticotropic Hormone in Y1 Mouse Adrenocortical Tumor Cells

New perspectives in signaling mediated by receptors coupled to stimulatory G protein: the emerging significance of cAMP eï¬„ux and extracellular cAMP-adenosine pathway

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