Inhibition of replication of normal adrenocortical cells in culture by adrenocorticotropin.

Ramachandran, J.; Suyama, Alan

doi:10.1073/pnas.72.1.113

Cited by 141 publications

(58 citation statements)

References 23 publications

(14 reference statements)

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“…Physiological ACTH levels are unable to induce compensatory adrenal hyperplasia after unilateral adrenalectomy in hypophysectomized animals (52). In vitro, inhibition of adrenal cell proliferation by physiological ACTH concentrations has been reported, and even pharmacological doses of ACTH induce only moderate cell growth (53). In accord with this findings, activating point mutations of neither the ACTH receptor nor the a-chain of Gs have been identified in benign or malignant adrenocortical tumors (50, 54±56).…”

Section: Acth-receptor Mutations In Adrenal Tumorssupporting

confidence: 67%

ACTH-receptor expression, regulation and role in adrenocortial tumor formation

Beuschlein

Faßnacht

Klink

et al. 2001

European Journal of Endocrinology

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The regulation of the ACTH-receptor gene is unique in that it is up-regulated by its own ligand, ACTH. Ligand-induced up-regulation of ACTH-receptor expression may be an important adaptive process directed towards optimizing adrenal responsiveness to ACTH in the context of physiological stress and the maintenance of metabolic homeostasis in which the adrenals play a pivotal role. Whereas enhancement by ligand-induced up-regulation permits a more efficient and rapid glucocorticoid response, negative feedback regulation of glucocorticoids in the hypothalamus and pituitary inhibits ACTH secretion and allows a balanced adrenal response to stress. Since the cloning of the promoter region of the ACTH receptor, considerable progress in the understanding of the regulatory processes has been made. The effects of ACTH on ACTH-receptor expression is dependent on cAMP, probably mediated through AP-1.The profound effect of three SF-1-binding sites in the ACTH-receptor promoter was demonstrated by deletion experiments. Conversely, ACTH-receptor expression can be suppressed by adrenal-specific transcription factors,like DAX-1.Despite an extensive search, no activating ACTH-receptor mutations have been found in adrenal tumors,excluding the ACTH receptor as a relevant oncogene in adrenal tumorigenesis. However, the ACTH receptor may act as a differentiation factor as suggested by LOH in adrenal carcinomas with an undifferentiated tumor type.In benign adrenal tumors, a strong correlation between ACTH-receptor expression and expression of P450 steroidogenic enzymes is evident. This close regulative relationship is lost in adrenal carcinoma, probably as a result of tumor dedifferentiation. Down-regulation of ACTH-receptor expression in normal and neoplastic tissue can be achieved by adrenostatic compounds such as aminoglutethimide and metyrapone.

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Section: Acth-receptor Mutations In Adrenal Tumorssupporting

confidence: 67%

ACTH-receptor expression, regulation and role in adrenocortial tumor formation

Beuschlein

Faßnacht

Klink

et al. 2001

European Journal of Endocrinology

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“…We have also confirmed that apart from the effect of CER and desCER on adrenocortical steroidogenesis, both polypeptides directly inhibit proliferative activity of the studied cells (20). Thus, as far as proliferative activity is concerned, both CER and desCER have ACTH-like effects, which are known to directly inhibit mitotic activity of adrenocortical cells (38,39).…”

Section: Discussionsupporting

confidence: 64%

Cerebellin and des-cerebellin exert ACTH-like effects on corticosterone secretion and the intracellular signaling pathway gene expression in cultured rat adrenocortical cells - DNA microarray and QPCR studies

Ruciński

Ziółkowska²,

Szyszka³

et al. 2009

Int J Mol Med

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Abstract. Precerebellins (Cbln) belong to the C1q/TNF superfamily of secreted proteins which have diverse functions. They are abundantly expressed in the cerebellum, however, three of them are also expressed in the rat adrenal gland. All members of the Cbln family form homomeric and heteromeric complexes with each other in vitro and it was suggested that such complexes play a crucial role in normal development of the cerebellum. The aim of our study was to investigate whether Cbln1-derived peptides, cerebellin (CER) and des-Ser 1 -cerebellin (desCER) are involved in regulating biological functions of rat adrenocortical cells. In the primary culture of rat adrenocortical cells, 24 h exposure to CER or desCER notably stimulated corticosterone output and inhibited proliferative activity and similar effects were evoked by ACTH. To study gene transcript regulation by CER, desCER and ACTH, we applied Oligo GEArray ® DNA Microarray: Rat Signal Transduction Pathway Finder™. In relation to the control culture, 13 of the 113 transcripts present on the array were differentially expressed. These transcripts were either up-or down-regulated by ACTH and/or CER or desCER treatment. Validation of DNA Microarray data by QPCR revealed that only 5 of 13 genes studied were differentially expressed. Of those genes, Fos and Icam1 were up-regulated and Egr1 was down-regulated by ACTH, CER and desCER. The remaining two genes, Fasn (insulin signaling pathway) and Hspb1 (HSP27) (stress signaling pathway), were regulated only by CER and desCER, but not by ACTH. Thus, both CER and desCER have effects similar to and different from corticotrophin on the intracellular signaling pathway gene expression in cultured rat adrenocortical cells.

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“…Adrenal glands from adult male Sprague-Dawley rats (350-400 g) were decapsulated and digested with collagenase and DNase as described (13). The cells were suspended in medium 199 containing 10% fetal bovine serum and 0.004% garamycin (Schering) at a concentration 7.5 X 105 cells per ml and incubated overnight (18 hr) in sterile bacterial Petri dishes (no.…”

Section: Methodsmentioning

confidence: 99%

Characterization of corticotropin receptors on adrenocortical cells.

Buckley¹,

Ramachandran²

1981

Proc. Natl. Acad. Sci. U.S.A.

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138

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The binding ofcorticotropin (ACTH) to receptors on isolated rat adrenocortical cells was investigated with the aid of [['25I]ITyro, Phe2, Nle4]ACTH-(1-38) (1'I-ACTH analog) which retained full biological potency and had a specific radioactivity of 1800 ± 75 Ci/mmol. Binding was highly specific to adrenocortical cells, and the radioactive peptide was displaced by low concentrations ofACTH but not by other basic peptides. Bind Despite numerous attempts to investigate corticotropin (ACTH) receptors by direct binding methods, detection and characterization ofthe physiologically relevant receptors for the hormone has proved to be a formidable task. The two major difficulties encountered in binding studies with ACTH are the extraordinary propensity of the hormone to bind to inert materials and nonreceptor components of the target tissue, and the low biological potencies of the radiolabeled ACTH preparations generally used in binding studies (1-4).The "2I-labeled ACTH (125I-ACTH) preparations used by Lefkowitz et aL (1) and Ontjes et aL (3) had biological activities of32 and 15 units/mg, respectively, compared to a value of200 units/mg for unmodified ACTH reported by Rae and Schimmer (5), as measured by the stimulation of adenylate cyclase in adrenocortical cell membrane fractions. McIlhinney and Schulster (6, 7) prepared '"I-ACTH having 50% of the steroidogenic activity of the native hormone by the lactoperoxidase method.Structure-function studies (5,8,9) have shown that the loss of biological potency of ACTH results from the introduction of a bulky iodine atom into the tyrosine residue in position 2 and the oxidation of the methionine residue in position 4. We recently circumvented these difficulties by synthesizing an analog of the hormone in which the tyrosine in position 2 is replaced by phenylalanine and the methionine in position 4 is replaced by norleucine (10). This peptide, referred to hereafter as ACTH analog, was shown to be equipotent with ACTH in stimulating steroidogenesis in adrenocortical cells. We have also shown that iodination of the ACTH analog and purification by reversephase high-pressure liquid chromatography (HPLC) yields 125I-ACTH analog with the theoretically attainable specific radioactivity and full biological potency (11). By the use of this radioligand we have succeeded in identifying the specific receptors for the hormone on rat adrenocortical cells. MATERIALS AND METHODS125I-ACTH Analog. [Phe2, Nle4]ACTH-(1-38) was synthesized by the solid-phase method and purified as described (10).[[251I]ITyr23, Phe2, Nle4]ACTH-(1-38), the 125I-ACTH analog, was prepared by the chloramine-T method and separated from free iodide by gel filtration on Sephadex LH-20 as described (11). It was stored at 4°C and freshly purified by reverse-phase HPLC for each experiment (11). The HPLC solvents were removed by lyophilization to 1/10th the original volume and the labeled peptide was diluted with medium 199 (GIBCO) containing 0.5% bovine serum albumin purified as described (12), and 0.01% bacitracin (A...

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Inhibition of replication of normal adrenocortical cells in culture by adrenocorticotropin.

Cited by 141 publications

References 23 publications

ACTH-receptor expression, regulation and role in adrenocortial tumor formation

ACTH-receptor expression, regulation and role in adrenocortial tumor formation

Cerebellin and des-cerebellin exert ACTH-like effects on corticosterone secretion and the intracellular signaling pathway gene expression in cultured rat adrenocortical cells - DNA microarray and QPCR studies

Characterization of corticotropin receptors on adrenocortical cells.

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