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PubMed1994

[The clinical significance serum N-POMC level in lung cancer patients].

Serum N-POMC level of 103 cases of lung cancer were measured in our hospital. The results were as follows: The lung cancer group, 50.5%, of patienst has an N-PONC level above the normal upper limit. The percentages of the N-POMC levels above the normal limit in lung cancers, such as: squamous-cell carcinoma, adenocarcinoma, SCLC and undifferentiated carcinoma were 52.2%, 50.0%, 47.3% and 57.1%, respectively. There was no statistically significant difference of N-POMC levels among these kinds of lung cancers, Eleven of 18 cases of SCLC patients in stage IIIb or IV, and 3 of 9 cases of SCLC patients in stage IIIa had N-POMC levels above the upper normal limit. Could serum N-POMC be one of the indexes for assisting the diagnosis and prognosis of lung cancer needs further investigation. Cases with carcinoid, thymoma and neurofibroma had higher N-POMC levels too. Six patients had Cushing syndrome.

Adenocarcinoma↗
PubMed1994

Proopiomelanocortin-derived peptides.

Cloning of the cDNA of POMC mRNA led to the characterization of the ACTH precursor and established the molecular links between ACTH, beta LPH and gamma LPH, and beta end. Further previously unidentified POMC-derived peptides were also unravelled, including the N-terminal fragment and the JP. POMC is a precursor polypeptide that contains the amino acid sequences of numerous small polypeptide products. It contains eight pairs of basic amino acids and one sequence of four basic amino acids, which are the sites of cleavage for the recently identified prohormone convertases (PC1 and PC2), which have different specificities. PC1 but not PC2 is found in corticotroph cells of the anterior pituitary and cleaves POMC to generate NT, JP, ACTH, beta LPH and small amounts of gamma LPH and beta end. In the melanotroph cells of the intermediate pituitary, both PC1 and PC2 are present. The proteolysis of POMC is thus more extensive, resulting in a series of smaller peptides including gamma MSHs, CLIP, alpha MSH, beta MSH, beta end, and beta end. Equimolar amounts (because they are all products of the same precursor) of the POMC peptides are released into the blood by exocytosis from corticotroph cells of the anterior pituitary. No physiological role has been definitively identified for any of these products other than ACTH. POMC peptides have been assayed in human blood by specific radioimmunoassay (RIA). In most circumstances, the concentrations of all these peptides are perfectly correlated. Therefore, for practical reasons, LPH RIA is widely used as an indicator of overall corticotroph function. In rare cases, the correlation between the POMC peptides is disrupted by a general disorder selectively modifying the metabolism of the different members of the family as in chronic renal failure, or in tumors where POMC processing is abnormal. Examples include pituitary macroadenomas, some silent corticotroph adenomas, and most frequently non-pituitary tumors responsible for ectopic ACTH syndrome. These pathologies can lead to the formation and secretion into blood of CLIP and beta MSH, or alternatively POMC may be underprocessed and secreted intact. An elegant approach, specific IRMA, has been developed to directly recognize unprocessed POMC in blood.

Animals↗
PubMed1994

Upregulation of the POMC gene in rats by a neurotoxicant which targets motoneurones.

Immunocytochemistry and histochemical in situ hybridisation were used to detect POMC-derived peptides (beta-endorphin and alpha-MSH) and POMC mRNA respectively, in the lumbar spinal cord of adult rats. In normal rats the incidence of ventral horn cells which expressed the peptides or mRNA was negligible. However after treatment with IDPN a neurotoxicant which targets the motoneurones the peptides and POMC mRNA were detectable in over 65% of ventral horn motoneurones. After treatment with 1,3 DNB a neurotoxicant which does not target motoneurones immunostaining for the peptides and mRNA was negligible. Thus chemical intoxication of the motoneurones causes upregulation of the POMC gene.

Animals↗
PubMed1994

Comparison of in vivo and in vitro corticotropin-releasing hormone-stimulated release of proopiomelanocortin-derived peptides in cats.

In 6 cats, the effect of IV administration of various concentrations of ovine corticotropin-releasing hormone (oCRH) on plasma concentrations of cortisol, alpha-melanocyte-stimulating hormone (alpha-MSH), and adrenocorticotropic hormone (ACTH) was measured. After administration of 1.0 microgram of oCRH/kg of body weight, significant (P < 0.05) increases in plasma cortisol, alpha-MSH, and ACTH concentrations were observed. After administration of 0.1 microgram of oCRH/kg, significant increases were found only for cortisol and ACTH concentrations. In vitro release of ACTH from dispersed feline pars distalis cells in primary culture stimulated by oCRH and arginine vasopressin (AVP) was dose-dependent. Maximal stimulation was achieved by 1 nM oCRH or 100 nM AVP. The oCRH-stimulated ACTH release was partially inhibited by dexamethasone, and AVP-induced release was completely inhibited. Pars intermedia cells released 20 times as much alpha-MSH as ACTH. A dose-dependent inhibition of alpha-MSH release was induced by the dopamine agonist, bromocriptine. This inhibition could be partially abolished by coincubation with haloperidol. Bromocriptine had no effect on release of ACTH. In conclusion, oCRH stimulates the pars distalis and pars intermedia of the pituitary gland of cats. Release of ACTH is stimulated by a direct effect on the pars distalis. In addition, in cats, oCRH is a more potent secretagogue than is AVP. The MSH release from the pars intermedia is sensitive to dopaminergic inhibition, indicating that dopamine may have a central role in regulation of MSH secretion in cats.

Adrenocorticotropic Hormone↗
PubMed1993

Quantitative and sensitive northern blot hybridization using PCR-generated DNA probes labeled with digoxigenin by nick translation.

Northern blot hybridization is one of the most convenient methods of detecting an mRNA. Nonradioactive Northern blotting using digoxigenin (DIG) is becoming widely applied because it is rapid and safe. Previous studies have indicated that DIG-labeled RNA probes are suitable for Northern blot hybridization. Here, the application of PCR-generated double-stranded DNA probes labeled with DIG by nick translation is described. DNA probes were synthesized by PCR, then labeled with DIG by nick translation. Northern blot hybridization was performed using the DIG-labeled DNA probes, and the signals were detected by means of a chemiluminescent reaction. A low amount of DIG-dUTP in the labeling reaction resulted in excellent Northern blots with low background. Densitometric analysis of the blots showed that the mRNA concentrations could be determined by densitometric analysis. The sensitivity of the DIG-Northern system was comparable to Northern blotting using 32P and was sufficiently sensitive to detect low-abundance mRNA.

Animals↗
PubMed1994

Cyclic AMP and ethanol interact to control apoptosis and differentiation in hypothalamic beta-endorphin neurons.

In this study we have determined the role of cyclic AMP on the function and differentiation of beta-endorphin (beta-EP) neurons in rat fetal hypothalamic cell cultures. Addition of Bt2cAMP or the cAMP elevating agent, forskolin, in cultures, dose and time dependently increased beta-endorphin secretion. The increased beta-EP secretion after Bt2cAMP or forskolin treatment was associated with proopiomelanocortin gene expression, enhanced neurite growth, and increased neuronal viability. Determination of internucleosomal cleavage of DNA by agarose gel electrophoresis revealed that apoptosis occurred in hypothalamic neurons during the first 6-8 days in culture. Addition of Bt2cAMP during this developmental period inhibited DNA degradation in hypothalamic neurons. Furthermore, incubation with various doses of ethanol, which is known to reduce intracellular levels of Bt2cAMP, increased DNA degradation in these cells. Ethanol-induced DNA degradation was blocked by concomitant incubation with Bt2cAMP. Histochemical identification of apoptotic cells following ethanol and Bt2cAMP treatments further revealed that apoptosis occurred in beta-EP neurons during the developmental period, and that ethanol increased and Bt2cAMP reduced apoptotic beta-EP cell numbers. These results suggest that ethanol neurotoxicity on beta-EP neurons during early neuronal differentiation involves an apoptotic process and that the cAMP signaling system plays an important role in controlling apoptosis and differentiation of the beta-EP neuronal system.

Animals↗
PubMed1994

Effect of POMC-derived peptides on corticosterone secretion during the stress hypo-responsive period in rat.

During the stress hyporesponsive period (postnatal days 2-10), the stimulation of corticosterone secretion by ACTH is very low. In our study, we have observed that administration of ACTH during 3 consecutive days is followed by a striking increase in corticosterone response to an acute ACTH test. A comparable potentiation of corticosterone secretion was observed after a similar treatment with Lys gamma 3-MSH. The 3 day-treatment with each peptide induced an increase in adrenal weight. Similar data were obtained with alpha-MSH. However, corticosterone response to ACTH was not significantly altered following the same pattern of alpha-MSH administration.

Adrenal Cortex↗
PubMed1994

The proopiomelanocortin (POMC) gene expression of AtT20 mouse pituitary cells is dependent on cell culture conditions.

We have compared the properties of AtT20 cells cultivated in a Dulbecco's modified Eagles medium containing 10% fetal calf serum (FCS) and of AtT20 cells adapted to a chemically better defined medium with transferrin, albumin, insulin, sodium selenit and 0.2% FCS. Our interest was focused on the hypothalamo-pituitary-adrenal axis (HPA) involved adrenocorticotropic hormone (ACTH) and the potent opioid peptide beta-endorphin (beta-END). There were no differences in basal secretion of ACTH and beta-END by cells cultivated in medium containing 10% or 0.2% serum, respectively. In combination to the decreased proliferation activity of AtT20 cells, grown in the serum-reduced medium we found a strongly enhanced ACTH secretion activity stimulated by the corticotropin releasing hormone (CRH) in contrast to normally cultivated AtT20 cells (10% serum). In addition, the proopiomelanocortin (POMC) gene expression was significantly down regulated in serum-reduced medium and was normalized again after further cultivation in a 10% serum containing medium. This leads to the conclusion that under standard conditions (10% serum) the gene transcription is increased by hitherto uncharacterized modulators present in the serum. The unexpected unchanged amounts of ACTH and beta-End could be the result of increased protein convertases activities. These enzymes are responsible for the POMC precursor processing into beta-End and ACTH.

Animals↗
PubMed1994

Endoproteolytic processing of proopiomelanocortin and prohormone convertases 1 and 2 in neuroendocrine cells overexpressing prohormone convertases 1 or 2.

AtT-20 mouse corticotrope tumor cell lines overexpressing the prohormone convertases PC1 or PC2 were established and used to examine prohormone and prohormone convertase biosynthetic processing. On a molar basis, wild-type AtT-20 cells synthesize about 20% as much PC1 as the endogenous prohormone, proopiomelanocortin (POMC). Kinetic, oligosaccharide, and temperature blockade analyses established that proPC1 is converted to PC1 in the endoplasmic reticulum at a rate independent of the level of PC1 or PC2 expression. In contrast, proPC2 is converted to PC2 primarily in a post-trans-Golgi compartment. PC1 is further shortened from its COOH-terminal end in a post-trans-Golgi compartment in a step that is accelerated at higher levels of PC1 expression, but unaltered by PC2 overexpression. The initial steps in POMC processing are speeded up by overexpression of PC1, and overexpression of PC1 leads to more extensive cleavage of POMC to smaller products. However, even when the rate of PC1 synthesis exceeds that for POMC by 2-fold, PC1 does not cleave the Lys-Lys or Arg-Lys bonds cleaved upon overexpression of PC2.

Animals↗
PubMed1994

Plasma concentrations of immunoreactive proopiomelanocortin peptides and cortisol in clinically normal cats.

We measured immunoreactive (IR) plasma concentrations of the proopiomelanocortin (POMC)-derived peptides (adrenocorticotropic hormone [ACTH]; beta-endorphin/beta-lipotropin [beta END/beta LPH]; and alpha-melanocyte stimulating hormone [alpha MSH]) and of cortisol in 100 clinically normal cats. Median plasma concentration of IR-ACTH was 2.7 pmol/L (range, < or = 1.1 to 22 pmol/L), of beta END/beta LPH was 28 pmol/L (range, 3.8 to 130 pmol/L), of alpha MSH was 36 pmol/L (range, < or = 3.6 to 200 pmol/L), and of cortisol was 35 nmol/L (range, 5 to 140 nmol/L). Plasma concentrations of IR-ACTH, alpha MSH, and beta END/beta LPH were at or below the assay sensitivity in 34, 3, and 0% of the cats, respectively. We did not detect a correlation between plasma concentrations of IR-ACTH and beta END/beta LPH (r = 0.23) or between plasma concentrations of IR-ACTH and alpha MSH (r = 0.19). However, there was a significant (P < 0.001) correlation between plasma concentrations of IR-beta END/beta LPH and alpha MSH (r = 0.81). There was not a significant correlation between plasma concentration of cortisol and plasma concentration of any of the IR-POMC peptides. High plasma concentrations of IR-alpha MSH and beta END, POMC peptides secreted predominantly by melanotrophs in other species, indicate that clinically normal cats have an actively secreting pars intermedia.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗
PubMed1993

Post-translational processing of proopiomelanocortin (POMC) in mouse pituitary melanotroph tumors induced by a POMC-simian virus 40 large T antigen transgene.

Mice harboring a transgene composed of proopiomelanocortin (POMC) gene promoter sequences (nucleotides -706 to +64) ligated to the simian virus (SV) 40 early gene encoding large T antigen developed large POMC-expressing pituitary tumors. Histologically the tumors arose from the intermediate lobe, contained nuclear SV40 T antigen and POMC peptides, but did not express other pituitary hormones. POMC processing in the pituitary tumors was indistinguishable from normal mouse intermediate lobe melanotrophs and was characterized by high proportions of acetylated and carboxyl-terminal shortened beta-endorphins, and amino-terminal acetylated alpha-melanocyte-stimulating hormone, and virtually no adrenocorticotropic hormone (ACTH)(1-39), beta-lipotropin, or POMC. The tumors contained abundant levels of mRNA for the prohormone convertase PC2 and undetectable levels of PC1. Normal mouse neurointermediate lobe also has a high ratio of PC2/PC1 expression that is distinct from the relative abundance of PC1 in anterior lobe and AtT-20 corticotroph cells. In contrast, extracts from tumors transplanted subcutaneously in nude mice contained predominantly nonacetylated forms of beta-endorphin(1-31) and -(1-27), very little ACTH(1-39), almost no corticotropin-like intermediate peptide or alpha-melanocyte-stimulating hormone, and higher proportions of intact POMC. Surprisingly, despite the less efficient proteolytic cleavage, a transplanted tumor expressed both PC1 and PC2. These studies are the first biochemical documentation of a melanotroph pituitary tumor in a rodent species and provide a new model for the investigation of pituitary oncogenesis and the molecular basis of tissue-specific prohormone post-translational processing.

Adrenocorticotropic Hormone↗
PubMed1993

Detection of proopiomelanocortin-derived antigens in normal and pathologic human skin.

We investigated the presence of proopiomelanocortin (POMC) products in sections of skin from normal subjects and patients with neoplastic and non-neoplastic cutaneous disorders. Antibodies specific against adrenocorticotropin, beta-melanotropin, and beta-endorphin were used for detection and characterization of cell types bearing POMC peptides. POMC products were not observed in sections of normal skin from the corporal (non-scalp) areas (six cases), whereas the hair follicles of scalp skin exhibited positive immunostains that were readily apparent (four cases). POMC products were frequently detected in corporal skin affected by diseases (13 of 26 cases), for example, psoriatic keratinocytes, the inflammatory infiltrate in scarring alopecia, nevocytes, the epithelial cell nests of basal cell carcinoma, and melanoma cells. Further tests were performed in keloids, a primary reactive skin disorder, to evaluate whether POMC accumulation represented a disease-related phenomenon or an expression of normal cutaneous reactivity. POMC products were consistently detected (10 of 11 cases) in the keratinocytes and mononuclear cells at keloid lesions. Thus these observations indicate that POMC products may accumulate locally in lesional skin representing, presumably, a novel cutaneous response to injury. The broad spectrum of POMC products detected suggests that these arise from production in situ (expression of the POMC gene itself) by human skin.

Adrenocorticotropic Hormone↗
PubMed1993

The prohormone convertases PC1 and PC2 mediate distinct endoproteolytic cleavages in a strict temporal order during proopiomelanocortin biosynthetic processing.

Two subtilisin-like endoproteases called PC1 and PC2 are distributed in a tissue-specific manner in the pituitary and in the brain. AtT-20 cells and corticotropes of the anterior pituitary express primarily PC1 and perform a limited number of cleavages of the proopiomelanocortin (POMC) precursor during biosynthesis. Melanotropes of the intermediate pituitary express both PC1 and PC2 and perform a more extensive set of cleavages during the biosynthetic processing of POMC. To investigate the role of PC2 in the biosynthetic processing of POMC, AtT-20 mouse corticotropes were stably transfected with a full length PC2 cDNA. The AtT-20 cells expressing PC2 acquired the ability to perform all the additional cleavages seen in the intermediate pituitary, but did not acquire the ability to alpha-N-acetylate the product peptides. The kinetics of the earliest steps in biosynthetic processing were unaltered by the expression of PC2, and the changes due to PC2 expression were seen only in the middle and late steps in biosynthetic processing. Thus, both the identity of the final product peptides and the kinetics of the processing steps in the AtT-20 cells expressing PC2 fit the patterns expected for melanotropes of the intermediate pituitary.

Adrenocorticotropic Hormone↗
PubMed1993

Processing of proopiomelanocortin by insulin secretory granule proinsulin processing endopeptidases.

A lysed preparation of isolated insulin secretory granules efficiently cleaved murine proopiomelanocortin (mPOMC) at physiologically important Lys-Arg processing sites. This processing was mostly attributed to an activity that co-eluted with the proinsulin processing type-II endopeptidase from anion exchange chromatography (Lys-Arg-directed; Davidson, H. W., Rhodes, C. J., and Hutton, J. C. (1988) Nature 333, 93-96). The principal peptide hormone products generated by the insulin secretory granule lysate were identified by specific radioimmunoassay and NH2-terminal microsequencing analysis of high performance liquid chromatography-separated products as alpha-melanocyte-stimulating hormone, corticotropin-like intermediate, gamma-lipotropin, beta-endorphin-(1-31), 18-kDa NH2-terminal fragment and, to a lesser extent, adrenocorticotrophin and beta-lipotropin. This processing had an acidic pH optimum (pH 5-5.5) and was Ca(2+)-dependent (K0.5 activation = 5-80 microM). With increasing Ca2+ concentrations there was an increase in the extent to which mPOMC was processed. The in vitro processing of mPOMC by the insulin secretory granule endopeptidase activity reported here is in excellent agreement with the in vivo processing of this prohormone by a combination of PC2 and PC3, candidates of prohormone endpeptidase, in gene transfer studies with cells that express the regulated secretory pathway (Thomas, L., Leduc, R., Thorne, B. A., Smeekens, S. S., Steiner, D. F., and Thomas, G. (1991) Proc. Natl. Acad. Sci. U.S.A. 88, 5297-5301).

Adrenocorticotropic Hormone↗