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At least 127 records · Page 7Linked to original sources
PubMed1992

Ectopic corticotropin-releasing hormone produced by a transfected cell line chronically activates the pituitary-adrenal axis in transkaryotic rats.

Hypothalamic CRH is the primary positive regulatory factor of the pituitary-adrenal axis. The purpose of our study was to analyze the chronic effects of CRH on the production and secretion of POMC peptides from both the anterior lobe (AL) and neurointermediate lobe (NIL) of the pituitary by mimicking the syndrome of ectopic CRH secretion from neuroendocrine tumors. We first generated stably transfected W2 medullary thyroid carcinoma cell lines with a rat CRH expression vector under the transcriptional control of a cytomegalovirus gene promoter. These cell lines constitutively expressed the foreign gene, accurately processed the encoded prepro-CRH, and secreted biologically active CRH with an estimated potency equivalent to that of synthetic CRH-(1-41)NH2. The cell line designated W2CRH-7 was implanted sc in the syngeneic rat strain WAG/Rij and produced tumors that abundantly secreted CRH into the peripheral circulation. Four weeks postimplantation, W2CRH-7, but not wild-type W2, cells caused significant increases in the AL content of beta-endorphin-like immunoreactivity comparable to that caused by adrenalectomy (ADX). Plasma ACTH and serum beta-endorphin-like immunoreactivity were increased to a greater extent by ADX than by W2CRH-7 cell implantation. The NIL of both male and female rats showed either no change or a tendency to decreased beta-endorphin concentrations with no change in the acetylation or carboxy-shortening profiles judged by cation exchange chromatography in response to the ectopic CRH treatment. Rats of both sexes maintained a profound activation of the pituitary adrenal axis up to 16 weeks postimplantation, with normalized adrenal gland weights 5 times that of controls. The chronic secretion of CRH by W2CRH-7 cells resulted in a complete cessation of body growth in all rats up to the maximum time tested of 16 weeks. The lack of growth was partly ameliorated by concomitant ADX, suggesting an important role for adrenal glucocorticoids in these effects. We conclude that 1) the transplantable W2CRH-7 cell line provides a highly effective and reproducible means of sustained CRH treatment that mimics the syndrome of ectopic CRH expression by neuroendocrine tumors; 2) AL corticotrophs respond to chronic CRH by a sustained production and secretion of POMC peptides, leading to a marked adrenal cortical hyperplasia, with no evidence of biologically significant desensitization; 3) chronic CRH tends to decrease the NIL content of beta-endorphin,with remarkably little effect on posttranslational processing; and 4) the syndrome of chronic ectopic CRH in WAG/Rij rats includes a cessation of body growth at least partly due to products of the adrenal glands.

Adrenalectomy↗
PubMed1992

Lymphocyte-derived adrenocorticotropin is insufficient to stimulate adrenal steroidogenesis in hypophysectomized rats.

Cells of the immune system can produce and respond to peptide hormones associated with the endocrine system. However, the physiological significance of these endocrine-immune interactions is not known. It has been postulated that cells of the immune system, when stimulated with viruses that induce interferon-alpha, produce sufficient levels of ACTH to stimulate adrenal steroidogenesis and, thus, function as an auxiliary source of ACTH that may have a role in the response to stress. However, we have confirmed that levels of ACTH-related peptides produced by immunocompetent cells are far lower than those produced by the pituitary, raising questions about the ability of lymphocyte-derived ACTH to stimulate adrenal function. Furthermore, we have rigorously examined this issue using intact and hypophysectomized rats treated with Newcastle disease virus. Although high levels of interferon-alpha were produced by both intact and hypophysectomized rats, and the plasma corticosterone concentration increased dramatically in intact animals, corticosterone remained undetectable in hypophysectomized rats. The lack of a corticosterone response in these animals was not due to adrenal insensitivity to ACTH, as shown by a normal rise in corticosterone following Cosyntropin injection 8 h after hypophysectomy. The findings demonstrate that levels of ACTH produced by nonpituitary sources in response to viral infection are not sufficient to stimulate adrenal steroidogenesis.

Adrenal Cortex Hormones↗
PubMed1992

Effect of implantation of dexamethasone adjacent to the paraventricular nucleus on messenger ribonucleic acid for corticotropin-releasing hormone and proopiomelanocortin during late gestation in fetal sheep.

Glucocorticoids act upon the hypothalamic paraventricular nucleus (PVN) and anterior pituitary in a classic negative feedback loop to regulate ACTH biosynthesis and secretion. Evidence exists to indicate that glucocorticoid feedback may be attenuated during late gestation in the sheep fetus to allow the preterm rise in fetal plasma cortisol necessary for parturition in this species. The present studies were undertaken to determine the effect of glucocorticoids placed adjacent to the fetal PVN on messenger RNA (mRNA) for CRH in the PVN and mRNA for POMC in the anterior pituitary during late gestation. We performed our studies at two critical stages during late gestation to determine if gestational age related changes occur in the efficacy of negative feedback regulation of expression of CRH and subsequently POMC. Dexamethasone (DEX) implants were placed bilaterally 2 mm lateral to the fetal PVN at 105 to 107 days gestational age (dGA; group I, n = 4) and 121-123 dGA (group II; n = 4). Gestational-age matched, sham implanted fetuses were used as controls (CONT) for both groups (n = 4 per group). Fetuses were recovered at 126-128 (group I) and 136 dGA (group II). Fetal PVN were isolated by micropunching, and the anterior pituitary was separated from neurointermediate and posterior lobes after necropsy. Total RNA was subjected to Northern analysis using specific complementary DNA probes to CRH and POMC, and specific message was normalized to actin mRNA content in each individual sample. Anterior pituitary POMC mRNA was not different in DEX fetuses compared to CONT for either group I (78 +/- 26% of CONT; mean +/- SEM) or group II (84 +/- 17% of CONT). PVN CRH mRNA content was lower in DEX fetuses in group I (28 +/- 14% of CONT; P less than or equal to 0.01) and group II (65 +/- 12% of CONT; P less than or equal to 0.01). The degree to which DEX suppressed mRNA for CRH was greater in group I compared to group II (P less than or equal to 0.05). We conclude that 1) CRH expression in the PVN of fetal sheep is suppressible by glucocorticoids; 2) suppression can occur directly at the level of the PVN and 3) that the efficacy of negative feedback decreases with increasing gestational age. Furthermore, the lack of effect of hypothalamic administration of DEX on anterior pituitary POMC mRNA indicates that basal expression of POMC in fetal sheep may be independent from support from the PVN at this stage of gestation.

Animals↗
PubMed1992

Transcriptional and posttranscriptional regulation of the proopiomelanocortin gene in the pars intermedia of the pituitary gland of Xenopus laevis.

In the melanotrope cells of the intermediate pituitary gland of the amphibian Xenopus laevis, expression of the POMC gene is under physiological control, i.e. it is 20- to 30-fold higher in animals adapted to a black background compared to animals adapted to a white background. To investigate whether changes in POMC messenger RNA stability contribute to this difference in expression, a steady state kinetic model for mRNA degradation was used to determine the half-life of POMC mRNA during the induction and deinduction of POMC gene expression in melanotrope cells. During induction of the POMC gene the half-life of POMC mRNA was 3- to 4-fold longer than during deinduction. This difference in mRNA stability is, however, not sufficient to account for the 20- to 30-fold difference in the steady state levels of POMC mRNA between the two physiological conditions. Results from experiments with the protein synthesis inhibitor cycloheximide and the mRNA synthesis inhibitor 5,6-dichloro-1-beta-D-ribofuranosylbenzidimidazole suggest 1) that during induction of POMC gene expression no de novo protein synthesis is required and, 2) that deinduction of POMC gene expression requires transcriptional activation of an mRNA-degradation system. Pulse-labeling experiments with [3H]uridine showed that in neurointermediate lobes of white-adapted animals there is an 8-fold higher amount of newly synthesized POMC mRNA than in lobes of black animals. This suggests a fast in vitro induction of POMC gene transcription. The dopamine D2-receptor agonist apomorphine decreased POMC mRNA biosynthesis about 5-fold, which confirms that regulation of POMC gene expression includes a transcriptional component. In conclusion, our results demonstrate that during the physiological process of background adaptation the regulation of POMC gene expression in Xenopus melanotrope cells is exerted by alterations in POMC gene transcription as well as in POMC mRNA stability.

Animals↗
PubMed1992

Proopiomelanocortin gene expression in a distinct population of rat spleen and lung leukocytes.

Existence of proopiomelanocortin (POMC) messenger RNA (mRNA) and related peptides in extrapituitary sites has been demonstrated in immune cells, although the particular type of immune cell has been the source of considerable debate. Specifically, double labeling studies have shown that POMC peptide expressing cells in the spleen represent a subpopulation of red pulp macrophages, while splenic lymphocyte areas are POMC negative. In addition, it has also been reported that peripheral blood leukocytes express the POMC gene. Using a sensitive solution hybridization technique with a POMC exon-1 RNA probe, we detected 70 +/- 20 fg and 65 +/- 5 fg POMC mRNA per microgram total RNA in whole spleen and lung, respectively, approximately 20,000-fold lower concentrations than found in the neurointermediate lobe of the pituitary. The presence of nuclease protected full length exon-1 bands, rather than the 5' truncated POMC RNAs seen in many nonpituitary tissues, indicates transcription initiation at the normal pituitary POMC promoter site in lung and spleen. In order to localize POMC gene expression in these tissues we employed an in situ hybridization method. There was an intense signal in a small population of large mononuclear cells scattered throughout the splenic red pulp and lung parenchyma. In the lung, these cells were concentrated in the periarteriolar zone in a manner suggestive of migration from the intravascular lumen. These cells had a histomorphology suggestive of monocyte-macrophages. POMC mRNA was undetectable in the splenic white pulp and bronchus-associated lymphoid tissue, indicating an absence of POMC gene expression in splenic and lung lymphocytes. Immunocytochemical studies suggested that POMC-positive cells made up a subpopulation of cells expressing the rat monocyte-macrophage markers ED1 and ED2. Similarly, the distribution of Jenner-Giemsa stained monocyte-macrophages appeared to overlap with POMC positive cells. Studies with anti-rat beta-endorphin antisera revealed scattered cells in the splenic red pulp and lung parenchyma, suggesting that the POMC mRNA is translated in these cells. In summary, POMC mRNA is expressed in a small population of monocyte-macrophage-like cells in lung and spleen but not in lymphocytes in these tissues.

Animals↗
PubMed1992

A certain step of proteolytic processing of proopiomelanocortin occurs during the transition between two distinct stages of secretory granule maturation in rat anterior pituitary corticotrophs.

To obtain antibodies specific for precursor POMC and its cleaved peptides, we prepared synthetic peptides corresponding to the cleavage site (ST-1) between ACTH and beta-lipotropic hormone moieties of POMC and to amidated joining peptide (JP; ST-3) and generated their polyclonal antibodies in rabbits. The anti-ST-1 serum immunoprecipitated only POMC in the extract of AtT-20 cells. In addition to a similar immunoprecipitation examination, an immunoabsorption test showed that anti-ST-3 serum recognizes cleaved peptides, 16K amino-terminal peptide, and JP, but not POMC precursor. Double immunolabeling with gold particles of different sizes for the precursor POMC and its cleaved peptides revealed that the former was localized in electron-dense secretory granules, whereas the latter was found in the electron-lucent secretory granules in the same ultrathin cryosections. Colocalization of POMC and its cleaved peptides in the same secretory granules was rarely observed. Only POMC immunolabeling was detected in the Golgi cisternae. These results suggest that a certain step of proteolytic processing of POMC occurs in the secretory granules during the transition between the two distinct stages of secretory granule maturation in the rat anterior pituitary corticotroph.

Adrenocorticotropic Hormone↗
PubMed1992

Aging abolishes the estradiol-induced suppression and diurnal rhythm of proopiomelanocortin gene expression in the arcuate nucleus.

The diurnal rhythms of many physiological functions are disrupted during aging. Underlying these disruptions are age-related alterations in the activity of neurotransmitters and/or their receptors. Estradiol has a significant influence on the pattern of the diurnal rhythms in neurotransmitter function, and responsiveness to estradiol changes with age. We assessed POMC mRNA levels in the arcuate nucleus of young, middle-aged, and old female rats to determine whether aging alters the diurnal rhythm of POMC gene expression in ovariectomized rats and/or changes the responsiveness to estradiol. In addition, we measured serum LH, PRL, and corticosterone levels to evaluate any age-associated interactions between these hormones and POMC mRNA levels. In young animals, estradiol treatment induced a diurnal rhythm and suppressed mean levels of POMC mRNA. In the middle-aged and old rats, the ability of estradiol to suppress POMC mRNA levels and to allow the expression of a diurnal rhythm of POMC mRNA was abolished. Although age-associated changes occurred in serum concentrations of LH, PRL, and corticosterone, they did not correlate with the changes in POMC gene expression. Therefore, our data demonstrate that age-related changes in hypothalamic POMC gene expression do not determine the changes in pituitary hormone secretion. Instead, they suggest that fundamental changes in diurnal function or in the biological clock underlie and differentially regulate the age-related changes in POMC gene expression and LH, PRL, and corticosterone secretion.

Aging↗
PubMed1991

Receptors for corticotropin-releasing hormone in human pituitary: binding characteristics and autoradiographic localization to immunocytochemically defined proopiomelanocortin cells.

Using autoradiography combined with immunocytochemistry, we demonstrated that the target cells of CRH in the human pituitary were proopiomelanocortin cells. Scatchard analysis of [125I]Tyr0-oCRH saturation binding revealed the presence of one class of saturable, high affinity sites on pituitary tissue homogenate. The equilibrium dissociation constant (Kd) for [125I]Tyr0-oCRH ranged from 1.1-1.6 nM, and the receptor density was between 200-350 fmol/mg protein. Fixation of cryostat sections with 4% paraformaldehyde before tracer incubation improved both tissue preservation and localization of the CRH receptor at the cellular level. Additional postfixation with 1% glutaraldehyde inhibited tracer diffusion during subsequent immunocytochemistry and autoradiography. [125I]Tyr0-oCRH was found in cytoplasmic inclusions or at the cell periphery of ACTH/beta-endorphin cells in the anterior pituitary. Single cells of the posterior pituitary were also CRH receptor positive. Cells staining for PRL or GH were CRH receptor negative. We conclude that CRH binds only to high affinity receptors on ACTH/beta-endorphin cells in the human pituitary.

Adrenocorticotropic Hormone↗
PubMed1992

Growth hormone-releasing hormone transcripts in human pituitary adenomas.

We have investigated the possibility that local production of GHRH within the adenohypophysis could be an aetiological factor in the development of human pituitary somatotroph and other tumours. We examined 51 human pituitary adenomas for GHRH transcripts using in situ hybridization histochemistry. GHRH transcripts were identified in 13 of 17 somatotroph adenomas, 4 of 10 corticotrophs, 1 of 6 lactotrophs and 1 of 18 endocrinologically inactive adenomas. In 11 GHRH-expressing somatotroph adenomas, SRIH transcripts were also identified. In all cases except one (a corticotroph adenoma) the average number of GHRH transcripts exceeded that found in the arcuate nucleus of simultaneously hybridized rat brain sections. In some pituitary adenomas, GHRH transcripts were clearly localized to a discrete subpopulation of cells and in these, the amount of GHRH mRNA per cell was comparable to that found in the GHRH-expressing cells of the rat arcuate nucleus. Although we have not directly demonstrated an association between the two, the identification of localized, high level GHRH gene expression in somatotroph adenomas suggests that GHRH may have a role in pituitary adenoma formation.

Adenoma↗
PubMed1992

Steroid hormones regulate the release of immunoreactive beta-endorphin from the Ishikawa human endometrial cell line.

Immunoreactive beta-endorphin (IR-beta END) is present in human endometrium. Several indirect lines of evidence suggest that endometrial beta END is under steroid hormone control, i.e. IR-beta END is detectable in the secretory, but not the proliferative, endometrium, and progesterone administration increases the concentration of IR-beta END in uterine secretions of ovariectomized gilts. To study the effect of steroid hormones on endometrial beta END, we first questioned whether Ishikawa human endometrial adenocarcinoma cells (which respond to steroid hormones) express the proopiomelanocortin (POMC) gene. Indeed, on Northern blot analysis, a RNA similar or identical in size to pituitary POMC mRNA was present in Ishikawa cell RNA extracts. IR-beta END was also present in Ishikawa cell extracts and culture medium, which coeluted with synthetic human beta END in a Sephadex G-50 column. Ishikawa cells released most of their IR-beta END into the culture medium. Estradiol decreased the release of IR-beta END from Ishikawa cells, an effect that was dependent upon dose and time. The maximal effect was observed after a 4-day exposure to 10 nM estradiol (44 +/- 6% of the control value; n = 6; P less than 0.001). This effect was almost completely counteracted by a 100-fold excess of the antiestrogen 4-hydroxytamoxifen. Progesterone and dihydrotestosterone did not have a statistically significant effect on IR-beta END release. Dexamethasone had effects similar to those of estradiol, i.e. decreased the release of IR-beta END in a time- and dose-dependent manner. The maximal effect was detected after a 4-day exposure to 10 nM dexamethasone (53 +/- 6% of the control value; n = 6; P less than 0.001). Interestingly, the antiprogestin-antiglucocorticoid RU486 exhibited agonistic properties, i.e. diminished the release of IR-beta END in a time- and dose-dependent fashion, possibly via the glucocorticoid receptor. Its maximal effect was reached after a 4-day exposure to 10 nM RU486 (55 +/- 6% of the control value; n = 6; P less than 0.001). In conclusion, our data demonstrate that the release of IR-beta END from Ishikawa cells in culture is inhibited by estradiol and dexamethasone, suggesting that endometrial beta END is under estrogen and glucocorticoid regulation, as is the case with hypothalamic and pituitary POMC-derived peptides. This is the first time that the in vitro release of a peripheral-extracranial POMC-derived peptide has been found to be under the direct control of estrogens and glucocorticoids.

Dexamethasone↗
PubMed1992

One of the two trout proopiomelanocortin messenger RNAs potentially encodes new peptides.

POMC is the precursor for a number of biologically active peptides such as ACTH, alpha-MSH, beta-MSH, and beta-endorphin. It is well known that some of these peptides, especially beta-endorphin, are involved in the regulation of reproductive functions in mammals. In order to investigate the possible role of POMC-derived peptides in the control of fish reproduction, we have cloned and sequenced two different trout POMC cDNAs called POMC A and POMC B. These cDNAs exhibited limited sequence homology (44%). The deduced amino acid sequences also showed weak similarity (43%), despite the high conservation of some peptide sequences (alpha-MSH, beta-MSH, and beta-endorphin). The POMC A coding sequence exhibited an unusual length, generating the longest endorphin ever sequenced. The long carboxy-terminal part of the beta-endorphin A contained three potential dibasic cleavage sites, allowing the occurrence of three new peptides: EQWGREEGEE, ALGE, and YHFQG. Using in situ hybridization, we found that the two POMC genes were expressed in the same pituitary cells. POMC A mRNA was the only one detectable in the hypothalamus of sexually inactive fish, whereas the two POMC genes were expressed in the hypothalamus of sexually active fish. These results indicate that two functional POMC genes are present in the rainbow trout. In POMC neurons, the expression of the POMC B gene is likely to be under the control of sexual steroids.

Amino Acid Sequence↗
PubMed1992

Presence and regulation of a truncated proopiomelanocortin gene transcript in rat pancreatic islets.

The demonstration of proopiomelanocortin-(POMC-) derived peptides in the endocrine pancreas suggests a local biosynthesis of these peptides. Using Northern blot analysis we demonstrated a 800 nucleotide POMC-like mRNA species. The POMC-like mRNA was demonstrable in a part of the pancreatic islets by the in situ hybridization technique. A small number of single cells within the exocrine pancreas were also found to give positive hybridization signals. Isolated islets were incubated under normoglycemic conditions with dibutyryl-cAMP (3mM) or dexamethasone (0.1mM) for 4 h. Dibutyryl-cAMP significantly (p < 0.01) increased the POMC-like mRNA content to 177 +/- 39.1% of the control whereas dexamethasone decreased it to 66.9 +/- 11.4% of the control. In vivo treatment of adult rats with 80 micrograms dexamethasone over 3 days showed also a reduction of the POMC-like mRNA level in the islets. In conclusions, the POMC gene is expressed in adult rat islets and can be regulated by dexamethasone and dibutyryl-cAMP. Whether the truncated POMC-like mRNA reported here is the source of the biosynthetic POMC-like products detected in the islets is not yet known.

Animals↗
PubMed1992

Acute unilateral nephrectomy elicits a specific increase in plasma of peptides derived from the N-terminal region of proopiomelanocortin.

Acute unilateral nephrectomy (AUN) causes natriuresis from the contralateral kidney through neurohumoral reflex pathways that involve an increase in the plasma of peptides derived from the N-terminal region of the adrenocorticotropic hormone (ACTH)/beta-endorphin precursor proopiomelanocortin (POMC). To determine the specificity of these humoral changes, the concentrations in plasma of ACTH and two peptides arising from the N-terminal fragment (NTF) of POMC, NTF32-49 and gamma-melanocyte-stimulating hormone (gamma-MSH), and of another natriuretic peptide, atrial natriuretic peptide (ANP), were measured by RIA with highly specific antisera to these epitopes. Group I experiments followed the course of sodium excretion (UNaV) for 120 min after AUN or sham nephrectomy. UNaV more than doubled within 60 min of AUN, and this natriuresis was maintained for the remainder of the experiment, whereas UNaV in sham rats did not change. There was no difference in plasma immunoreactive (ir) ACTH or ir-ANP concentrations between sham and AUN rats 120 min after the procedure, but plasma ir-NTF concentration was double in AUN rats compared with sham (P < 0.03). In Group II experiments, animals were killed 30, 60, 90, or 120 min after AUN and the urinary response related to peptide concentrations in plasma. UNaV rose rapidly after AUN, reaching a maximum value within 45 min that again was double the control value and remained stable for the duration of the experiment, up to 120 min after AUN. There was no significant change in ir-ACTH or ir-ANP at any point after AUN compared with values in sham AUN rats. However, plasma concentrations of both ir-NTF and ir-gamma-MSH were elevated 30 min after AUN and reached values at 120 min that were again double the values in sham rats (P < 0.05 for both).(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Kidney Injury↗
PubMed1992

Analysis of gastrinomas by immunohistochemistry and in situ hybridization histochemistry.

Gastrinomas from 25 patients were examined by immunohistochemistry (IHC) and in situ hybridization histochemistry (ISH). Most patients (84%) presented with the Zollinger-Ellison syndrome. Six had multiple endocrine neoplasia type I (MEN-I). Twelve patients (48%) had duodenal primaries and 11 of 12 of these had metastases to regional lymph nodes and/or liver in spite of the small sizes of the primary tumors (mean size of 0.9 cm). Five patients had pancreatic gastrinomas and eight patients had metastatic tumor in regional lymph nodes or liver at surgery but a primary was not found. IHC and ISH analyses showed that all cases were positive for gastrin protein and 24 of 25 (96%) expressed gastrin mRNA that was easily detected in formalin-fixed, paraffin-embedded tissue sections. Both benign and malignant tumors expressed alpha subunit of human chorionic gonadotropin protein (alpha-HCG). However, only malignant gastrinomas (29%) expressed adrenocorticotropic hormone protein or proopiomelanocortin (POMC) mRNA. ISH and Northern hybridization analysis revealed that chromogranin A mRNA was the most common member of the chromogranin/secretogranin (Cg/Sg) family which was expressed in both benign and malignant gastrinomas. These results indicate that duodenal gastrinomas are common in both sporadic and MEN-1-associated cases, and small duodenal primaries may be associated with extensive regional lymph node and liver metastases. Expression of ACTH/POMC protein and mRNA was consistently associated only with malignant gastrinomas while gastrin protein, gastrin mRNA and Cgs/Sgs mRNAs were readily detected in both benign and malignant gastrinomas.

Adrenocorticotropic Hormone↗
PubMed1992

Proopiomelanocortin-derived peptides as tools of immune evasion for the human trematode Schistosoma mansoni.

Schistosomes are digenetic trematodes which share their life cycle between a definitive (vertebrate) and an intermediate (invertebrate) host. Their survival is highly dependent on their ability to reduce significantly the efficiency of the host defences. We have previously demonstrated the presence of POMC derived peptides (ACTH, alpha-MSH, beta-endorphin) in all stages of Schistosoma mansoni life cycle. Given the immunomodulatory properties of these peptides in vertebrates and invertebrates it has been postulated that they might be implicated in parasite immune evasion. We report the release of these neuropeptides during the cycle, associated with the inhibition by these peptides of the locomotory activity of immunocytes from both hosts, the hamster Mesocricetus auratus and the freshwater snail B. glabrata. The implication of these common signals in this new strategy of parasite adaptation is discussed.

Animals↗
PubMed1992

Inhibitory effects of proopiomelanocortin on cortical and medullary activity in the calf adrenal.

The effects of the infusion of ACTH1-24 and proopiomelanocortin on the denervated adrenal gland have been investigated in conscious 3-6 weeks-old calves by means of the adrenal-clamp technique. To prevent variation in the release of endogenous ACTH the pituitary stalk was cauterized during preparatory surgery. ACTH1-24 (5 ng/min per kg, i.v.) increased the output of cortisol from the adrenal by about 500 ng/min per kg body weight and this effect was rapidly reduced by simultaneous infusion of ovine proopiomelanocortin at 5 ng/min per kg. Release of met5-enkephalin and leu-enkephalin from the adrenal was reduced by ACTH1-24 (P less than 0.05) and this effect was enhanced significantly by additional infusion of proopiomelanocortin (P less than 0.02). However met5-enkephalin represented less than one-third of the met-enkephalin containing peptide released and the output of this pool was unaffected by infusion of ACTH. Proopiomelanocortin had no effect on met5-enkephalin production nor that of the total pool of met5-enkephalin containing peptides. It is concluded that ACTH reduced the quantity of pro-enkephalin processed to met5-enkephalin.

Adrenal Cortex↗
PubMed1992

Beta-adrenergic stimulation of cFOS via protein kinase A is mediated by cAMP regulatory element binding protein (CREB)-dependent and tissue-specific CREB-independent mechanisms in corticotrope cells.

Catecholamines stimulate proopiomelanocortin (POMC) gene expression in corticotrope cells, but the molecular mechanisms of these effects are not known. While beta-adrenergic receptors stimulate the protein kinase A (PKA) system, the POMC promoter does not have classical cAMP-response elements (CREs). Therefore, we investigated the induction of the c-fos protooncogen, previously shown to increase POMC transcription in AtT20 cells. In this corticotrope-derived cell line, we show that activation of beta-receptors with isoprenaline (Iso) induces a transient rise in c-fos mRNA levels. Gel mobility shift assays with a labeled AP1 consensus sequence (TGACTCA) showed induction of specific binding activity after Iso treatment. Cotransfection experiments with dominant inhibitory PKA mutants and reporter genes containing c-fos promoter sequences showed that c-fos induction by Iso is entirely dependent on a functional PKA activity. Furthermore, we show that beta-receptor induction of c-fos in corticotrophs is mediated by at least two distinct cAMP-responsive sequences. cAMP regulatory element binding (CREB)-dependent induction is observed on the CRE located at -60 bp on the c-fos promoter. A region located in the vicinity of the dyad symetry element (-290) is also found to mediate tissue-specific cAMP induction. Transcriptional activation by this site, although sensitive to PKA antagonism, is not blocked by CREB mutants.

Animals↗