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PubMed1991

Ectopic ACTH secretion. A misnomer.

Ectopic ACTH production is a common cause of Cushing's syndrome. In most patients, the neoplasm is obvious and is readily identified as the source of ACTH. However, in some patients, the neoplasm is not obvious and differentiating the tumor from a pituitary source is difficult. Current data demonstrate that virtually all normal tissues produce small amounts of a biologically inactive precursor ACTH molecule, probably proopiomelanocortin (POMC). All cancers produce this same substance in increased quantities. Selected cancers, correlated with histologic type, convert POMC to biologically active ACTH to produce the so-called ectopic ACTH syndrome. In this context, ectopic ACTH production is not ectopic.

ACTH Syndrome, Ectopic↗
PubMed1991

Ectopic secretion of peptides of the proopiomelanocortin family.

A wide spectrum of clinical and biochemical presentations characterize ectopic POMC syndrome. It is presently postulated that ectopic POMC production results from increased expression of the activity of a POMC gene normally occurring in a variety of tissues outside the pituitary gland. The syndrome is rapidly progressive and is characterized by severe clinical manifestations in patients with a more aggressively developing oat cell carcinoma of the lung. However, in patients with slower growing nonpituitary tumors, the presentation may overlap that seen in patients with pituitary ACTH-dependent Cushing's syndrome. In cases in which the biochemical testing results overlap with those seen in pituitary ACTH-dependent disease, a combination of lack of suppression with high-dose dexamethasone and absent response to CRH stimulation greatly increases the diagnostic accuracy. Abnormal alternative processing of POMC in nonpituitary neoplasms may render unusual POMC-derived peptides that could be used as markers in the diagnosis and follow-up of patients with this syndrome. The prognosis of patients afflicted with ectopic POMC syndrome is largely determined by the nature of the underlying tumor. However, the clinical course can be greatly modified by control of the metabolic manifestations of hypercortisolemia. A variety of surgical and pharmacologic options are available, including adrenalectomy and the use of adrenal inhibitors. Cushing's syndrome of long duration, the finding of ectopic pituitary adenomas, and the combined secretion of CRH and POMC by nonpituitary tumors constitute interesting variants of the classic picture.

ACTH Syndrome, Ectopic↗
PubMed1991

Opiate tolerance and dependence: recent findings and synthesis.

Recent studies have led to a greater understanding of the behavioral, cellular, and molecular mechanisms underlying opiate tolerance and physical dependence. Behavioral studies have demonstrated that both direct pharmacological effects and the learning of interactions between drug effects and environmental cues are important in these phenomena. Behavioral studies have also revealed that N-methyl-D-aspartate receptors may play a role in their development (or acquisition). Although in early cellular studies no consistent role was found for opioid receptors or endogenous opioid peptides in opiate tolerance and dependence, recent experiments suggest that beta-endorphin, enkephalin, and dynorphin neurons may indeed have a role. Finally, studies at the molecular level suggest that a functional decoupling of opioid receptors from GTP-binding proteins (G proteins) may be important. In this review, we discuss these disparate findings and present a synthesis that shows how they might together contribute to the phenomena of opiate tolerance and physical dependence.

Animals↗
PubMedDate not supplied

[ACTH of lymphocytic origin under normal and pathological conditions].

Evidence has accumulated that human peripheral blood mononuclear cells (PBMC) may release adrenocorticotropic hormone (ACTH) and endorphin-like peptides into the culture medium when stimulated with different substances such as Newcastle disease virus and the lipopolysaccharide of Escherichia coli. However, to our knowledge, no quantitative assessment of ACTH-LIR (like-immunoreactivity) in human PBMC has been reported. We thus utilized a radioimmunoassay for ACTH to find a median of 30 pg of ACTH-LIR in 10(7) PBMC of 11 normal subjects. ACTH-LIR was also detected in 7 different cell lines derived from patients with lymphoid and myeloid malignancies, two of them, JM and U937, showed values of 135 and 108 pg/10(7) cells respectively. Stimulation with IL-1 beta at the concentration of 1000 U/mL induced, after 48 h, a significant increase of intralymphocytic ACTH levels when compared to basal and 24 h values. The chromatographic characterization of this ACTH-LIR showed, at least, three molecular forms of immunoreactive ACTH; molecular weights were 31 kD POMC, 22 kD ACTH and 4.5 kD ACTH. We used northern blotting with human genomic DNA probe for POMC gene to evidence specific mRNA in PBMC; mRNA was also observed in a T lymphocyte cell line derived from a patient with lymphoma. We conclude that PBMC produce ACTH-LIR which may act as a paracrine immunomodulator similar to lymphokine and/or may signal the adrenal gland to secrete glucocorticoids.

Adrenocorticotropic Hormone↗
PubMed1991

Nucleotide sequence of cDNA coding for mink proopiomelanocortin (POMC) and its comparative analysis with POMC mRNA primary structures from pituitaries of other animal species and man.

cDNA for proopiomelanocortin (POMC) of mink has been cloned and sequenced. A comparative analysis of the primary structures of mRNAs coding for proopiomelanocortins of eight animal species and man has been performed. The analysis has revealed conserved and variable POMC mRNA regions. High variability of some of the regions is suggested to be due to the peculiarities of their structural organization. A putative mechanism responsible for the mutations in variable regions is proposed. A tree of the evolutionary relations of POMC has been developed.

Amino Acid Sequence↗
PubMed1991

The gene encoding proopiomelanocortin in the dog.

The regulation of the synthesis of ACTH in the dog is of interest for studies of the physiology of the pituitary-adrenocortical axis as well as for studies of the pathogenesis of pituitary-dependent hyperadrenocorticism. Despite this broad interest the nucleotide sequence encoding ACTH and its precursor proopiomelanocortin (POMC) is not known, nor is it clear whether there are differences in POMC mRNA from the anterior lobe or the intermediate lobe of the normal pituitary or from pituitary tumours causing ACTH excess. Following the preparation of a cDNA library from the canine intermediate lobe of the pituitary gland, the part of the mRNA that is translated into the proopiomelanocortin prohormone was amplified using a polymerase chain reaction. Sequence analysis revealed the highest homology with the porcine mRNA sequence. Translation in a single reading frame revealed highly homologous areas in the amino-terminal, carboxy-terminal, and ACTH part of the prohormone, whereas a high diversity was noticed at the sequence preceding ACTH and the beginning of beta-lipotropin. Northern blot analysis disclosed the presence of a POMC mRNA of approximately 1300 nucleotides. There were no size differences between the anterior lobe, intermediate lobe, and pituitary tumour derived POMC mRNA. The highest expression levels of POMC mRNA as related to the expression of the gene encoding glyceraldehyde-3-phosphate dehydrogenase were found in the intermediate lobe of the canine pituitary gland. It is concluded that excessive production of ACTH by pituitary tumours is not caused by relatively high expression levels or alterations in the size of mRNA.

Amino Acid Sequence↗
PubMedDate not supplied

[The endorphins of the epithelial and subepithelial structures of the rat small intestine and the evolutionary hypotheses of the formation of the mechanisms of the negative regulation of their synthesis].

The effects of the agonist of the glucocorticoid hormones dexamethasone and dopamine antagonist--haloperidol on the concentration of immunoreactive alpha-, beta- and gamma-endorphins in duodenum, ileum, and jejunum of rats were studied. Besides the extracts of the intestines, the immunoreactive endorphins were measured in the extracts of their mucosa-submucosa and muscle-serous layers, that allowed to separate the endorphin-producing cells of the nervous system (muscle-serous layer) from endorphin producing cells of endocrine and immune systems (mucosa-submucosa layer). The injection of dexamethasone (0.2 mg per rat, daily for 6 days) caused the reliable decrease in concentrations of all three types of endorphins in mucosa-submucosa and muscle-serous layer of duodenum, ileum, and jejunum. Under the action of haloperidol (0.6 mg per rat, daily for 6 days) the reliable increase of beta-endorphin concentration was noticed only in jejunum. The suggestion is made that two distinct subpopulations of endorphin-producing cells exist in the intestine: in one cells endorphin synthesis is regulated by glucocorticoids, as in the anterior lobe of pituitary, in the other cells the synthesis of endorphins is regulated by dopamine, as in the cells of the intermediate lobe of pituitary. It is suggested that both glucocorticoid and dopamine types of regulation of endorphins synthesis were formed in the intestine or even in the gastric cavity. In process of evolution the cells with glucocorticoid type of regulation gave rise to the anterior lobe of pituitary, the cells with the dopamine type of regulation--to the intermediate lobe.

Adrenalectomy↗
PubMed1991

Expression and processing of mouse proopiomelanocortin in bovine adrenal chromaffin cells. A model system to study tissue-specific prohormone processing.

Many neuroendocrine precursor proteins, such as proopiomelanocortin (POMC), are cleaved in a tissue specific manner at distinct pairs of basic amino acids. Elucidating the specificity of the prohormone endoprotease(s) is essential to understanding cleavage specificity. However, isolation of these enzymes has been difficult, due to the inability to distinguish authentic maturation enzyme from the many other trypsin-like activities present in tissue homogenates. Recently, a "signature" of the insulin cell endoprotease(s) was defined in vivo by assessing the processing of a series of mutant cleavage sites in a model prohormone, mouse POMC (mPOMC) (Thorne, B. A., and Thomas, G. (1990) J. Biol. Chem. 265, 8436-8443. To investigate mechanisms of tissue-specific processing, we sought to identify the endoprotease signature of a cell having a processing phenotype distinct from insulinoma cells. In this report, the cleavage site specificity of the endoprotease(s) expressed in bovine adrenal chromaffin cells is examined. High levels of mPOMC (1.6 pmol/10(6) cells) were expressed in these cells using a vaccinia virus vector, and the precursor was targeted to the regulated secretory pathway. Analysis of POMC-derived peptides revealed that chromaffin cells processed the prohormone to a set of peptides highly similar to anterior pituitary corticotrophs, including adrenocorticotropin hormone (ACTH) and beta-lipotropin, gamma-lipotropin, and beta-endorphin. This processing contrasted with the pattern of cleavage site utilization in Rin m5F insulinoma cells, which more closely resembled that of the intermediate pituitary melanotrophs. However, the processing preference for the sequences of pairs of basic amino acids (as tested using the entire series of mutant cleavage sites; -LysArg- (native), -ArgArg-, -ArgLys-, -LysLys-, -HisArg-, -MetArg- at the ACTH/beta-lipotropin junction and -LysLys- (native), -LysArg-, -ArgArg-, -ArgLys- in beta-endorphin) was the same in both insulinoma and adrenal chromaffin cells, suggesting recognition and cleavage by similar enzymes in both cell types. The cell-specific processing of mPOMC may thus result from expression of a common core set of processing enzymes and factors unique to each cell type affecting the enzyme accessibility to precursor cleavage sites.

Adrenal Medulla↗
PubMed1991

Specific inhibition of protein kinase A in granulosa cells abolishes gonadotropin regulation of the proopiomelanocortin promoter.

Gonadotropins (follicle-stimulating hormone (FSH), luteinizing hormone, and human chorionic gonadotropin) and beta-adrenergic agonists have been shown to stimulate expression of the proopiomelanocortin (POMC) gene in ovarian granulosa cells. The current studies investigate the intracellular mechanisms by which gonadotropins regulate gene expression. Primary cultures of rat granulosa cells were transfected with the plasmid POMC-CAT-150, which expresses the chloramphenicol acetyltransferase (CAT) reporter gene under the regulation of the rat POMC 5'-flanking region. CAT activity was stimulated by treatment of the cells with either 20 ng/ml FSH or 1 microM isoproterenol. To assess the role of protein kinase A (ATP:protein phosphotransferase; EC 2.7.1.37) in the gonadotropin and adrenergic response, an expression vector, MtR-AB, encoding a mutant RI regulatory subunit was cotransfected with POMC-CAT-150. The mutant protein kinase A regulatory subunit encoded by MtR-AB lacks functional cAMP-binding sites but effectively binds and specifically inhibits the catalytic activity of protein kinase A. The results of this analysis demonstrated that gonadotropin and adrenergic agonist stimulation of the POMC-CAT reporter construct in primary cultures of rat granulosa cells were abolished by cotransfection with MtR-AB; whereas a control SV40-promoter construct was unaffected by either gonadotropin treatment or cotransfection with MtR-AB. Basal expression directed by the POMC promoter was also decreased by cotransfection with the MtR-AB, implying that basal expression from the POMC promoter may also depend on protein kinase A. Deletion analysis of the POMC sequence indicated regions (-40 to -33 and +4 to +63) important for basal and FSH-stimulated expression. These studies suggest that both gonadotropin and adrenergic stimulation of the POMC promoter are mediated by protein kinase A and that regions proximal to the promoter are essential for gonadotropin-regulated expression from the promoter.

Animals↗
PubMed1990

The helminth Schistosoma mansoni expresses a peptide similar to human beta-endorphin and possesses a proopiomelanocortin-related gene.

Opioid peptides, a group of transmitter substances with a high degree of phylogenic conservation, have many different functions, including a role in modulation of cells of the immune system. We have postulated the existence of such peptides in the parasite Schistosoma mansoni in view of their possible role in host-parasite interactions. In this report we show that beta-endorphin, which is a member of the opiate family and is derived from the proopiomelanocortin (POMC) precursor, is present in S. mansoni. Southern blots of cercarial genomic DNA, hybridized with two oligonucleotide probes complementary to highly conserved POMC sequences, showed a POMC-related gene in this trematode. Northern blot analysis of adult worm RNA indicated that this gene was actively transcribed. Significant amounts of beta-endorphin, adrenocorticotropin (ACTH), and alpha-melanocyte stimulating hormone (alpha-MSH) were detected in all developmental stages of the parasite by radioimmunoassays with the use of antisera to human peptides. By means of reverse-phase high-performance liquid chromatography (HPLC), we found that the parasite beta-endorphin-like material and the human opiate have a high degree of homology. These results appear to constitute the first demonstration of a POMC-related gene transcribed in an invertebrate.

Adrenocorticotropic Hormone↗
PubMed1991

Expression of pre-opiomelanocortin (POMC) mRNA in undifferentiated and in vitro differentiated human neuroblastoma cell lines.

Several human neuroblastoma cell lines express transcripts of the proopiomelanocortin (POMC) gene of 0.8 kb and 9.5 kb, thus different from the characteristic pituitary 1.2 kb POMC mRNA. The expression of POMC mRNA decreases when the cell lines are differentiated with retinoic acid or alpha-difluoromethylornithine. Since both POMC and MYCN genes are present on the same chromosome segment (2p23), it is possible that the 2 genes are coamplified and coexpressed. Alternatively the expression of opiate peptides by neuroblastoma cells might act as an autocrine factor or it may modulate the action of tumour infiltrating lymphocytes.

Cell Differentiation↗
PubMed1990

An in vivo characterization of the cleavage site specificity of the insulin cell prohormone processing enzymes.

Most peptide hormones and neurotransmitters are synthesized as larger precursor proteins, which are post-translationally processed to mature bioactive products. An early event in prohormone maturation is endoproteolytic cleavage, occurring usually at pairs of basic amino acids (e.g. Lys-Arg). Since many of the characteristics of a prohormone endoprotease are unknown, distinguishing these enzymes from other cellular proteases in vitro has been difficult. In this report, the substrate specificity of a model prohormone processing system, the insulinoma cell line Rin m5F, was characterized in vivo to establish a set of criteria by which putative proinsulin endoproteases may be assessed. To determine the role of composition of the paired basic amino acid site in directing cleavage, a series of mutant prohormones containing altered cleavage sites was constructed and expressed in Rin m5F cells. Proopiomelanocortin (POMC) was used as a substrate since this prohormone was previously shown to be processed by these cells. To control for positional effects, all four permutations of lysine and arginine (Lys-Arg, Arg-Arg, Arg-Lys, and Lys-Lys) were introduced at both the efficiently processed cleavage site separating the ACTH and beta-lipotropin (beta-LPH) domains of POMC and at the inefficiently processed site in the beta-endorphin sequence near the COOH-terminus of the precursor. His-Arg and Met-Arg sites were also introduced at the ACTH/beta-LPH junction to assess the requirement for paired lysines and arginines. Identification of POMC-derived peptides demonstrated efficient processing of Lys-Arg and inefficient processing of Lys-Lys and Arg-Lys sites at both positions in the prohormone. The Arg-Arg sequence, however, was processed in a position-dependent manner, being efficiently cleaved between ACTH and beta-LPH but only about 50% processed within beta-endorphin. His-Arg was not cleaved in Rin m5F cells, although surprisingly Met-Arg was partially processed. These results indicate a strict preference of the insulinoma prohormone endoprotease(s) for paired basic amino acids ending in arginine, but that processing efficiency of some sequences may be modulated by location within the precursor molecule.

Amino Acid Sequence↗
PubMedDate not supplied

[Expression in Escherichia coli of hybrid genes containing sequences coding the bovine adrenocorticotropic hormone].

E. coli strains producing a hybrid protein, containing adrenocorticotropic hormone (ACTH) and protein A of S. aureus was obtained. The sequence coding for ACTH was obtained from the bovine proopiomelanocortin cDNA and, after the modification of the 5'- and 3'-terminal parts, was linked with the protein A gene and its derivatives due to synthetic adaptors. Three forms of ACTH gene, coding this hormone with differing N-terminal amino acid were used to construct the fusion gene. The hybrid proteins contain Asp-Pro or (Asp)4-Lys sequences for obtaining ACTH by acid or enterokinase treatment, respectively. It is shown that each of the constructed plasmids direct the synthesis of hybrid protein in E. coli. This protein was purified by the use of IgG-sepharose. The level of the expression of the hybrid protein is 4 mg/l of the bacterial culture. Most of the synthesized protein is secreted into the periplasmic space.

Adrenocorticotropic Hormone↗