Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Peptides that are derived from the processing of proopiomelanocortin were isolated in pure form from the brain of the frog Rana ridibunda. The primary structure of the most abundant of those peptides was established as: Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val. This amino acid sequence is identical to that of mammalian and frog pituitary alpha-melanocyte-stimulating hormone (MSH) and the peptide co-eluted with synthetic desacetyl alpha-MSH, indicating that it is COOH-terminally alpha-amidated. A second component, which exhibited a shorter retention time, co-eluted with the glycine-extended form of desacetyl alpha-MSH [ACTH(1-14)]. The primary structure of the third peptide isolated in pure form from the brain extract was established as: Lys-Tyr-Val-Met-Ser-His-Phe-Arg-Trp-Asn-Lys-Phe-NH2. This sequence corresponds to Lys-gamma 1-MSH as predicted from the nucleotide sequence of frog proopiomelanocortin. The presence of substantial amounts of desacetyl alpha-MSH and Lys-gamma 1-MSH in the frog brain supports the concept that, in amphibia, melanotropins may act as neurotransmitters and/or neuromodulators as well as hormonal peptides.
Brain Res Mol Brain Res 1992 Sep
PMID:Isolation and structural characterization of peptides related to alpha- and gamma-melanocyte-stimulating hormone (MSH) from the frog brain. 133 55

These studies were undertaken to evaluate the role of protein kinase C (PKC) in the regulation by arginine vasopressin (AVP) of adrenocorticotropin (ACTH) secretion from the ovine anterior pituitary. AVP caused the rapid translocation of PKC from the cytosol to the cell membrane in ovine anterior pituitary cells that was maximal at 5 min. This phenomenon, which is a known concomitant of C-kinase activation, was produced to a greater extent by phorbol 12-myristate 13-acetate (PMA) but not by corticotropin-releasing factor (CRF). To determine whether AVP activated corticotrope PKC, we assessed the ability of three different PKC inhibitors (H-7, sphingosine, and retinal) to modify basal, AVP-, PMA-, and CRF-stimulated ACTH release. In addition to inhibiting the in vitro activity of purified PKC, each compound also caused in vitro inhibition of the protein kinase A (PKA) catalytic subunit, indicating that none could be considered to be a specific inhibitor of PKC and the PKA catalytic subunit. As determined by the mean IC50 values required for the in vitro inhibition of PKC and the PKA catalytic subunit, sphingosine was judged to be the most selective and H-7 the least selective PKC inhibitor. A 4 h exposure to each inhibitor caused a dose-dependent increase in basal ACTH release and attenuation of both AVP- and PMA-stimulated ACTH release. H-7 and retinal, in concentrations that caused a 20-50% inhibition of PKA, also attenuated CRF-stimulated ACTH release; however, this effect was not observed with sphingosine in concentrations that caused only a 10-20% inhibition of PKA. We conclude that: (1) AVP causes the direct activation of PKC in the ovine anterior pituitary and that C kinase activation is important in mediating the effect of AVP on ACTH release; (2) the finding that inhibition of PKC elevates ACTH suggests that basal ACTH secretion is also partly regulated by PKC; (3) since CRF does not cause PKC translocation in ovine anterior pituitary cells, it is unlikely that PKC plays a physiological role in the action of CRF on the corticotrope; (4) the finding that H-7 and retinal attenuate CRF-stimulated ACTH secretion suggests that CRF activates PKA in corticotropes.
Mol Cell Endocrinol 1992 Sep
PMID:Evidence that the stimulation by arginine vasopressin of the release of adrenocorticotropin from the ovine anterior pituitary involves the activation of protein kinase C. 133 7

The Y1 adrenocortical tumor cell mutants, Kin-7 and Kin-8, harbor point mutations in the regulatory subunit (RI) of the type 1 cAMP-dependent protein kinase (cAMPdPK) that render the enzyme resistant to activation by cAMP. These mutants also are resistant to many of the regulatory effects of ACTH and cAMP. In order to examine the causal relationships between the mutations in cAMPdPK and the resistance to ACTH and cAMP, the Kin mutants were transfected with expression vectors encoding wild type subunits of cAMPdPK in order to restore cAMP-responsive protein kinase activity. The transformants then were screened for the concomitant recovery of cellular responsiveness to ACTH and cAMP. In the mutant Kin-7, cAMP-responsive protein kinase activity was recovered after transfection with an expression vector encoding wild type mouse RI. Protein kinase activity in the mutant Kin-8 remained largely cAMP-resistant after transfection with the RI expression vector but could be rendered cAMP-responsive by transfection with an expression vector encoding the wild type catalytic subunit. The recovery of cAMP-responsive protein kinase activity was accompanied by the recovery of steroidogenic and morphological responses to ACTH and cAMP, suggesting that the cAMP-dependent signaling cascade plays an obligatory role in these actions of ACTH. The growth-regulatory effects of cAMP were not reversed with the recovery of cAMP-responsive protein kinase activity, suggesting that cAMP-resistant growth regulation results from second-site, adaptive mutations either in the original Kin mutant population or in the transformants. Studies on the conversion of 22(R)-hydroxycholesterol into steroid products in parent and mutant cells indicate that the Kin mutations reduce the steroidogenic capacity of the cell as well as inhibit the hormone- and cyclic nucleotide-dependent mobilization of substrate cholesterol.
Mol Endocrinol 1992 Oct
PMID:The causal relationship between mutations in cAMP-dependent protein kinase and the loss of adrenocorticotropin-regulated adrenocortical functions. 133 50

The product of the CYP11A gene, cholesterol side chain cleavage cytochrome P450, catalyzes the initial step of steroidogenesis. A major mechanism whereby steroid hydroxylase gene transcription is regulated in the adrenal cortex requires the pituitary peptide hormone, ACTH, which acts via cAMP. We have previously identified a transcriptional enhancer in the 5'-flanking sequence [-183 to -83 base pairs (bp)] of the bovine CYP11A gene, which activates transcription of a beta-globin promoter/reporter gene in transiently transfected mouse Y1 adrenocortical tumor cells in response to the activator of adenylate cyclase, forskolin. Further deletion analysis has located the minimal cAMP-responsive sequence (CRS) to -118 to -100 bp. Analysis of DNA-protein interactions using nuclear extracts from Y1 cells revealed two protein binding sites, which were shown by competition analysis to be closely related to the two protein binding sites identified previously in the CRS of the human CYP21 gene. Namely, within the cAMP responsive fragment -118 to -100 bp, a sequence with a high degree of similarity to the consensus binding sequence for the ubiquitous transcription factor Sp1 is present, and binding of protein to this site was abolished by competition with excess GC box oligonucleotide. The second partially overlapping site is located 3' of the putative Sp1-binding site and binds to a protein identical or closely related to a putative adrenal-specific protein. Whereas the adrenal-specific protein binding site of the CYP21 CRS was previously shown to be sufficient to confer cAMP-responsive activation of transcription, the homologous site within the CYP11A CRS appears to have an attenuating effect on transcription.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Endocrinol 1992 Oct
PMID:3',5'-cyclic adenosine monophosphate-dependent transcription of the CYP11A (cholesterol side chain cleavage cytochrome P450) gene involves a DNA response element containing a putative binding site for transcription factor Sp1. 133 53

Cholesterol ester hydrolase (CEH) activity was characterized in the porcine adrenal gland and experiments conducted to determine the nature of its hormonal regulation. CEH activity was studied in the 14,000 gmax pellet (F4) and in the 192,000 gmax supernatant (F6). Characteristics associated with pH optima, product formation with time, linearity with increasing protein concentration, and equilibration of exogenous cholesterol esters added in acetone with endogenous cholesterol esters were determined. Scatchard analyses of saturation data demonstrated two-site models, which indicated the presence of lower velocity lower Km enzymes (catalytic sites) (L-VKm) and higher velocity higher Km enzymes (catalytic sites) (H-VKm) in both subcellular fractions. Neither ACTH (0.4 micrograms/kg body weight) nor 30-min restraint affected CEH activities at 0.5, 2, and 5 h after injection or initiation of restraint. However, 1 h after a longer restraint period (45 min), F4 H-VKm CEH activity increased concomitantly with decreased F6 L-VKm (P = 0.003). More modest increases in F4 H-VKm (P = 0.03) were still apparent 1 h after the last of nine daily 45-min restraints. Bromocriptine (CB154, a dopamine agonist) administration for 6 days (9.6 mg/daily) reduced plasma prolactin (PRL) by 53% (P < 0.05), but had no effect on CEH activities. ACTH treatment to CB154-induced hypoprolactinemic barrows dramatically reduced F4 (63%) and F6 (49%) L-VKm CEH activity (P = 0.03). These data are the first concerned with regulation of adrenal CEH activity in swine, and are the first to evaluate in vivo treatments on in vitro CEH activity in any species evolutionarily higher than rodents. In vivo regulation of porcine adrenal CEH activity appears complex. Stressor-associated hormonal perturbations apparently must surpass a certain threshold of duration and/or magnitude before they alter CEH activity. Differing Km and Vmax of CEH within and between the two subcellular fractions studied and the differential responses to restraint stressor suggest that as many as four different enzymes with CEH activity are involved. Additionally, the combined effect of ACTH and CB154-induced hypoprolactinemia argues for an interrelated modulatory function of ACTH and PRL (or dopamine) on specific porcine adrenal CEH activities.
J Steroid Biochem Mol Biol 1992 Dec
PMID:Hormonal and stressor-associated changes in porcine adrenocortical cholesterol ester hydrolase activity. 133 79

Adjuvant arthritis (AA) in the rat leads to chronic stimulation of the hypothalamic-pituitary-adrenal (HPA) axis and the loss of its diurnal rhythmicity. We have investigated the effects of adrenalectomy (ADX) and different levels of corticosterone replacement upon plasma ACTH levels and anterior pituitary pro-opiomelanocortin (POMC), GH and prolactin mRNAs during the development of AA. In control ADX animals, we observed the negative feedback effects of exogenous corticosterone on plasma ACTH and anterior pituitary POMC mRNA. In the ADX animal with AA, however, the increased POMC mRNA which was observed was not reduced by exogenous corticosterone on day 7 of AA, although the negative feedback effect of corticosterone on plasma ACTH was intact. On day 14, however, even high dose corticosterone replacement failed to have a significant feedback effect on the raised levels of plasma ACTH. In control ADX animals, corticosterone replacement resulted in increased anterior pituitary GH mRNA and reduced prolactin mRNA. In contrast, in ADX animals with AA, GH mRNA was reduced and there was a further decrease in prolactin mRNA. In these animals, corticosterone replacement did not affect GH or prolactin mRNA expression. These data demonstrate a disruption of the normal mechanisms underlying feedback inhibition of the HPA axis by glucocorticoids during AA. Similarly, the glucocorticoid-dependent regulation of GH and prolactin mRNA expression is altered in AA.
J Mol Endocrinol 1992 Dec
PMID:Glucocorticoid-mediated responses of plasma ACTH and anterior pituitary pro-opiomelanocortin, growth hormone and prolactin mRNAs during adjuvant-induced arthritis in the rat. 133 26

The adrenal glomerulosa cell is a major site of action of angiotensin II (AII), which binds to AT1 receptors to stimulate phosphoinositide hydrolysis and Ca2+ mobilization, and the subsequent production of aldosterone. All also influences adrenal growth and proliferation and promotes thymidine incorporation in adrenocortical cells. In primary cultures of bovine glomerulosa cells, AII was found to induce the expression of several early growth response genes (c-fos, c-jun, JunB, and Krox 24). This effect of AII was dose-dependent and was blocked by [Sar1,IIe8] AII and the nonpeptide antagonist DuP 753, indicating that it is mediated by the AT1 subtype of the AII receptor. ACTH, which elevates cAMP in glomerulosa cells, was a relatively weak inducer of c-fos expression but was as potent as AII in stimulating the expression of JunB. ACTH did not further enhance the maximal effect of AII on c-fos expression. The role of the AII-induced cytoplasmic Ca2+ increase in generating the c-fos response was suggested by the ability of the Ca2+ ionophore ionomycin to induce c-fos expression. However, mobilization of intracellular Ca2+ by the Ca2+ ATPase inhibitor thapsigargin, as well as the stimulation of Ca2+ influx by depolarization with potassium, were less potent stimuli of c-fos expression. Omission of Ca2+ from the extracellular medium, which abolishes the plateau phase of the AII-induced Ca2+ signal without affecting the early increase due to Ca2+ mobilization, enhanced the early phase of the AII-induced c-fos response, indicating that Ca2+ also has an inhibitory effect on the early gene response. Activation of protein kinase C by phorbol 12-myristate, 13-acetate (PMA) also stimulated c-fos expression, but the combination of PMA and ionomycin did not further increase the c-fos response. Inhibition of protein kinase C by staurosporine, or its depletion by prolonged exposure to PMA, prevented the c-fos response to PMA but only partially inhibited the response to AII, suggesting the involvement of other factors in stimulus-transcription coupling from the AT1 receptor.
Mol Endocrinol 1992 Nov
PMID:Stimulation of early gene expression by angiotensin II in bovine adrenal glomerulosa cells: roles of calcium and protein kinase C. 133 25

The expression of kidney androgen-regulated protein (KAP) gene in mouse kidney is regulated in a multihormonal fashion. As determined by in situ hybridization analysis, epithelial cells of proximal convoluted tubules of cortical nephrons express KAP mRNA in response to androgenic stimulation while similar cells in the juxtamedullary S3 segment of the tubules express KAP mRNA under estrogenic and pituitary hormonal control. In situ hybridization analysis of kidney sections using hypophysectomized (hypox) mice resulted in a total absence of KAP mRNA suggesting the participation of a pituitary hormone(s) in the constitutive expression of KAP mRNA in S3 cells. Treatment of hypox mice with steroid hormones showed that androgens restored the ability of cortical tubule cells to synthesize KAP mRNA. Estrogen treatment, on the other hand, partially induced KAP gene expression only in S3 cells. These results indicated that the androgenic response of the gene is independent of pituitary function, while expression in S3 cells, although partially induced by the direct action of estrogens, is primarily regulated by a pituitary factor. In order to elucidate which hormone(s) is responsible for KAP gene expression in S3 cells, individual pituitary hormones were administered to hypox normal animals and to strains of mice genetically deficient in certain pituitary hormones. Surgically treated C57BL/6 female and male mice were implanted for 7 days with osmotic pumps containing individual pituitary hormones, after which the kidneys were analyzed by in situ hybridization. Mice injected with growth hormone (GH), corticotropin (ACTH), prolactin (PRL), or vehicle failed to express KAP mRNA. Mice treated with thyrotropin (TSH), follitropin (FSH), and lutropin (LH) exhibited high levels of KAP mRNA in S3 cells of females as well as in the renal cortex of male animals. Expression in the cortex in response to LH and FSH may be due to their gonadotropic effect on testosterone production. Similarly, contamination of TSH samples with small amounts of the gonadotropins may explain the cortical response to TSH. TSH produced the strongest response in S3 cells suggesting that it is responsible for the permissive effect of the pituitary on KAP gene expression. This conclusion was supported by studies performed with the dwarf mouse (dw/dw) which lacks PRL, GH, and TSH due to a mutation in the pit-1 gene. In situ hybridization analysis of dwarf mice kidney sections showed a complete lack of KAP gene expression. The possible participation of GH and PRL was eliminated on the basis of the hormone replacement studies.(ABSTRACT TRUNCATED AT 400 WORDS)
Mol Cell Endocrinol 1992 Nov
PMID:Effects of pituitary hormones on the cell-specific expression of the KAP gene. 133 21

The role of AII receptors subtypes, AT1 and AT2, in the regulation of aldosterone secretion was studied in adrenal glomerulosa cells and membranes from rats on normal and low sodium intake, using AII receptor subtype-specific antagonists. In adrenal glomerulosa cells, more than 90% of the receptors were AT1 and there was a good correlation between the potencies of the antagonists to inhibit ligand binding, and AII-stimulated aldosterone production and inositol phosphate formation. The inhibition of basal and ACTH-stimulated cAMP by AII was also abolished by the AT1, but not the AT2, antagonist. Sodium restriction for 6 days increased both receptor subtypes in the same proportion, but only the AT1 antagonist inhibited AII-stimulated aldosterone production. The data demonstrate that AT1 receptor mediates the regulatory actions of AII in the adrenal zona glomerulosa.
Mol Cell Endocrinol 1992 Dec
PMID:Role of angiotensin II receptor subtypes on the regulation of aldosterone secretion in the adrenal glomerulosa zone in the rat. 133 30

In previous studies, mutant clones (designated Y1DR) were isolated that resisted ACTH-induced homologous desensitization of adenylyl cyclase. The Y1DR mutation also conferred resistance to the homologous desensitization induced by agonist stimulation of transfected beta 2-adrenergic receptors. These observations suggested that ACTH and beta 2-adrenergic agonists homologously desensitized adenylyl cyclase in Y1 cells by a common mechanism. In the present study, parental Y1 cells (Y1DS) and the Y1DR mutant were transfected with the gene encoding the human dopamine D1 receptor and examined for regulation of adenylyl cyclase by dopaminergic agonists. Transformants were isolated from both cell lines and shown to respond to dopamine agonists with increases in adenylyl cyclase activity. Treatment of the Y1DS transformants with ACTH promoted a rapid, homologous desensitization of adenylyl cyclase and had little effect on the responses to dopamine or NaF; treatment of Y1DS with dopaminergic agonists promoted a slower rate of heterologous desensitization that diminished responsiveness of the adenylyl cyclase system to dopamine, ACTH, and NaF. Y1DR cells transfected with the dopamine D1 receptor were resistant to the heterologous desensitization of adenylyl cyclase induced by dopaminergic agonists. These latter observations suggest that the pathways of homologous desensitization and heterologous desensitization converge at a common point in the desensitization pathway defined by the DR mutation in Y1 cells.
Mol Endocrinol 1992 Jul
PMID:Heterologous desensitization of the human dopamine D1 receptor in Y1 adrenal cells and in a desensitization-resistant Y1 mutant. 135 41


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