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PubMed1996

Protein folding in the endoplasmic reticulum: lessons from the human chorionic gonadotropin beta subunit.

There have been few studies of protein folding in the endoplasmic reticulum of intact mammalian cells. In the one case where the in vivo and in vitro folding pathways of a mammalian secretory protein have been compared, the folding of the human chorionic gonadotropin beta subunit (hCG-beta), the order of formation of the detected folding intermediates is the same. The rate and efficiency with which multidomain proteins such as hCG-beta fold to native structure in intact cells is higher than in vitro, although intracellular rates of folding of the beta subunit can be approached in vitro in the presence of an optimal redox potential and protein disulfide isomerase. Understanding how proteins fold in vivo may provide a new way to diagnose and treat human illnesses that occur due to folding defects.

Chorionic Gonadotropin, beta Subunit, Human↗

PubMed1988

Isolation and characterization of the human chorionic gonadotropin beta subunit (CG beta) gene cluster: regulation of transcriptionally active CG beta gene by cyclic AMP.

The alpha and beta subunit genes encoding chorionic gonadotropin (CG) are regulated transcriptionally in placental cells by cyclic AMP (cAMP). The regulatory response sequences of the alpha gene have been studied extensively. Similar studies of the CG beta subunit (CG beta) gene have not been possible because transcriptionally active sequences have not been identified in the clones isolated to date. The CG beta subunit genes form a complex cluster of seven structurally similar genes that include six CG beta-like genes and a single luteinizing hormone beta subunit (LH beta) gene. We isolated overlapping clones containing the entire CG beta/LH beta gene cluster (68 kilobases) from a human genomic cosmid library. The organization of the gene cluster was similar to that found in previous analyses, as determined by Southern blots of genomic DNA, but differed from some of the gene assignments, as determined by fragments cloned in lambda phage. The 5'-flanking sequence of the most active CG beta gene (CG beta 5) was linked to the chloramphenicol acetyltransferase (CAT) coding sequence for analyses of transient expression in different cell types. CG beta CAT was expressed preferentially in JEG-3 choriocarcinoma cells, and expression was markedly stimulated by treatment with 8-bromo-cAMP. Deletion mutagenesis of the CG beta 5'-flanking sequence revealed that multiple regions were required for maximal expression. The kinetics for cAMP stimulation of alpha CAT and CG beta CAT expression were different, suggesting that different pathways may be involved in cAMP-stimulated expression of the alpha and CG beta genes.

Base Sequence↗

PubMed1995

Anti-HIV effect of beta subunit of human chorionic gonadotropin (beta hCG) in vitro.

Human chorionic gonadotropin (hCG)--a pregnancy-associated immunomodulating hormone--has been recently shown in vitro to suppress reverse transcriptase activity in chronically HIV-infected lymphocytes and monocytes and to block viral transmission resulting from cell-cell contact between virus-carrying lymphocytes and placental trophoblasts. In further pursuit of the query into the mechanism of action, purified alpha and beta subunits of hCG were tested for the inhibition of p24 gag protein synthesis in virus-producing ACH-2 lymphocytes and U1 monocytes. Unlike the alpha subunit, beta-hCG displayed a distinct U-shaped dose response, characteristic of the effect of dimer hCG. Maximum inhibition of viral expression has been achieved at 10-100 ng/ml, the concentration corresponding to blood levels of beta-hCG in pregnant women. The doses that were several logs higher of normal levels seemed to increase viral production in monocytes. The data presented supports our original observations regarding the effect of intact hCG on HIV replication. While the mechanism of action remains to be established, the results suggest that the virus-interfering activity of hCG is determined by hormone-specific beta chain but not by the alpha subunit--shared with the family of glycoprotein hormones from the pituitary--follicle-stimulating hormone, luteinizing hormone and thyrotropin.

Cell Division↗

PubMed2005

Importance of the detection method for intact dimeric human chorionic gonadotropin without interference with the free human chorionic gonadotropin beta subunit for pregnancy exclusion before liver transplantation in a woman with cholangiocarcinoma.

Assay of human chorionic gonadotropin (hCG) is mainly used for the detection and monitoring of pregnancy, and for the follow-up of trophoblastic tumors. The serum free beta-hCG subunit (hCGbeta) is also a tumor marker in many non-trophoblastic tumors, including gastrointestinal cancers. In this work, we compared the performance of several immunoassays for pregnancy exclusion before liver transplantation and in the follow-up of a woman with cholangiocarcinoma. Serum hCG was detected with the Abbott Testpack plus hCG-Combo and measured with four automated sandwich immunoassays: ADVIA-Centaur, ACS:180, AxSYM and Dimension. hCGbeta was determined by an automated fluorescence sandwich immunoassay (Kryptor-Free beta hCG) and with a specific immunoradiometric assay (ELSA-F beta hCG, Schering). The expression of hCG was also evaluated by immunohistochemistry on sections of intrahepatic cholangiocarcinoma cells and on peritoneal metastases. Before transplantation, discordant results were observed for pregnancy exclusion. Qualitative Testpack and Dimension tests detected no hCG-like immunoreactivity, whereas the ADVIA-Centaur, ACS:180 and AxSYM tests revealed positive levels. The same discrepancy was obtained in follow-up of the patient after liver transplantation. hCGbeta assay and immunohistochemical staining revealed tumor cell secretion of hCGbeta. In conclusion, a specific serum immunoassay for intact dimeric hCG without cross-reaction with hCGbeta should be adopted as routine policy for pregnancy exclusion before liver transplantation.

Adult↗

PubMedDate not supplied

Frequency and clinical significance of beta-subunit human chorionic gonadotropin expression in non-small cell lung cancer patients.

Human chorionic gonadotropin (HCG), a classic trophoblastic marker, has been found recently in many nontrophoblastic tumors. Previously we have found elevated serum betaHCG levels in 14% of small cell lung cancer patients. The aim of the present study was to assess the frequency and clinical significance of betaHCG expression in non-small cell lung tumors and in the sera of patients. 153 non-small cell lung cancer patients entered into this study. The control group consisted of 85 patients with benign lung diseases. Serum betaHCG elevation exceeding 5 mIU/ml was found in 3.5% of patients with benign lung diseases and in 12% of lung cancer patients (p = 0.03). Tumor analysis revealed the presence of betaHCG positivity in 28% of resected lung specimens. betaHCG positivity was found more often in adenocarcinoma than in squamous cell lung carcinoma both in tissue and in serum, the differences being not significant. Elevated serum betaHCG values were found more frequently in stage IV patients than in the remainder (p = 0.03). Response to chemotherapy (partial or minor response) was obtained more often in the patients with normal serum betaHCG than in those with serum betaHCG elevation (p = 0.03). We suppose that the ability to produce betaHCG is a rare but important biologic feature of lung carcinomas combined to some extent with chemoresistance.

Adult↗

PubMed1996

Novel covalent chaperone complexes associated with human chorionic gonadotropin beta subunit folding intermediates.

Molecular chaperones facilitate the folding of proteins in the endoplasmic reticulum (ER) of mammalian cells. The glycoprotein hormone chorionic gonadotropin beta subunit is a secretory protein whose folding in the ER has been demonstrated (Huth, J. R., Mountjoy, K., Perini, F., and Ruddon, R. W.(1992) J. Biol. Chem. 267, 8870-8879). Because folding of wild type hCG-beta subunit occurs in the ER with a t1/2 = 4-5 min, stable association of ER chaperones with hCG-beta have been difficult to detect probably because they have a short half-life. However, beta-chaperone complexes containing the ER chaperones BiP, ERp72, and ERp94 have been detected in slow folding mutants of hCG-beta subunit that lack both of the N-linked oligosaccharides (Feng, W., Matzuk, M. M., Mountjoy, K., Bedows, E., Ruddon, R. W., and Boime, I. (1995) J. Biol. Chem. 270, 11851-11859). The questions addressed here are 1) whether the detection of chaperone-containing complexes is related to the absence of carbohydrate or to the rate of hCG-beta subunit folding, 2) whether such complexes are dead-end or whether they lead to formation of a secreted, mature hCG-beta form, and 3) what the nature of the hCG-beta-chaperone binding is. The data obtained indicate that the amount of detectable hCG-beta-chaperone complexes correlates with the rate or extent of folding, that the complexes of hCG-beta with ER chaperones lead to the formation of secretable beta, and that the complexes of hCG-beta with chaperones involve the formation of intermolecular disulfide bonds.

Animals↗

PubMed1988

Origin and occurrence of human chorionic gonadotropin beta-subunit core fragment.

Human chorionic gonadotropin (hCG) beta-subunit core fragment (beta-fragment) is present in the urine of pregnant individuals as well as those with trophoblast disease and certain other cancers at concentrations 0.8 (early pregnancy) to 7 (second trimester pregnancy)-fold greater than that of hCG. The core fragment may be directly secreted by trophoblast tissue into the circulation or possibly originates from peripheral degradation of circulating hormone by the kidney. We examined the former hypothesis. We examined 24-h organ cultures of trophoblast tissue from first, second, and third trimester pregnancy. The media from this tissue contained hCG, free beta-subunit, and beta-fragment. The amount of beta-fragment present exceeded that of hCG, as was observed in second and third trimester pregnancy urine. The beta-fragment immunoreactive material produced by trophoblast tissue was compared to a standard preparation of urinary beta-fragment. The material in medium was identical to the standard beta-fragment in its elution pattern from a gel filtration column, from a reverse-phase HPLC column, from an ion-exchange gel, and from an immobilized lectin affinity column, and also by electrophoresis and immunoblotting with fragment-reactive monoclonal antibodies. We conclude that beta-fragment can also originate directly from trophoblast tissue, and could be the principal hCG beta-immunoreactive molecule secreted.

Chorionic Gonadotropin↗

PubMed2004

Expression of a recombinant bifunctional protein from a chimera of human lutropin receptor and human chorionic gonadotropin beta-subunit.

Human lutropin (hLH) and human chorionic gonadotropin (hCG) are structurally and functionally similar and play important roles in reproduction via a common gonadal receptor (LH-R). However, hormone specific hCG-beta subunit contains 24 additional amino acid carboxyl terminal peptide (CTP), which produce specific antibodies to hCG-beta with little cross-reaction with LH. A chimeric protein containing both hLH-R and hCG-beta would provide a unique bifunctional antigen for immunocontraception. In this study is described the synthesis of a chimeric DNA construct of full-length of hLH-receptor and hCG-beta and its expression in Sf9 cells to produce a bifunctional protein. Recombinant protein was recognized by antibodies to LH-R as well as anti-hCG-beta in Western Blots, thus indicating the preservation of immunological epitopes for both hLH-R and hCG-beta in the chimera. Specific ligand binding of recombinant hLH-R component was demonstrated by the displacement of bound labeled hCG at increasing concentrations of unlabeled hCG, indicating that, the presence of hCG-beta component of the chimera did not interfere with the binding of hCG to LH-R. hCG-beta was also present in the recombinant chimeric protein as shown by a specific hCG-beta chemiluminescence assay. Treatment of transfected Sf9 cells with hCG induced dose-dependent increase in the stimulation of intracellular cAMP production, which showed that the ligand binding had functional activity. These results demonstrate that the chimeric DNA construct of hLHR-hCG-beta expressed a bifunctional protein containing both hLH-R and hCG-beta activities, which could provide a unique potential antigen for immunocontraception in vertebrates.

Animals↗

PubMed1981

Serial beta-subunit human chorionic gonadotropin doubling time as a prognosticator of pregnancy outcome in an infertile population.

Prospective evaluation through the use of radioimmunoassay of the beta-subunit of human chorionic gonadotropin (beta-hCG) in blood samples obtained during the first 30 days of gestation was performed on an infertile population at high risk for pregnancy loss. Four hundred and fourteen samples in 281 pregnancies were analyzed. On the basis of single, random beta-hCG samples in asymptomatic patients, 77% of successful pregnancies and 59% of abortions were correctly identified. On the basis of beta-hCG doubling time (mean 2.2 days +/- 1.0 [2 SD]) computed from serial sampling, again in asymptomatic patients, 88% of successful pregnancies and 76% of abortions were correctly identified. beta-hCG doubling time appears to provide a reliable method of evaluating early pregnancy prognosis with significantly greater ability to identify problem pregnancies within the first 30 days of gestation than does single random hCG values.

Abortion, Incomplete↗

PubMed1989

[The value of determination of human chorionic gonadotropin beta subunit in extrauterine pregnancies].

The authors deal with the value of the avidin-biotin enzyme immunoassay (A-B-Elisa) which was introduced by them for the demonstration of human chorion gonadotropin beta subunit (HCG-b). It is pointed out that the possibility of the diagnosis of extrauterine pregnancy improved significantly by measuring the HCG-b level with A-B-ELISA method. The HCG-b hormone level over 5 mIU/ml refers to trophoblast activity and it is absolutely necessary to observe the patients in this case. In cases where the HCG-b level is low and the clinical symptoms are uncertain the patient must be kept under close observation and serial serum samples must be examined. Significant rise of HCG-b level refers to normal intrauterine pregnancy whereas a slightly rising, or unchanging or even decreasing hormone level suggest the possibility of extrauterine gravidity.

Biotin↗

PubMed1994

Misfolded human chorionic gonadotropin beta subunits are secreted from transfected Chinese hamster ovary cells.

There are six intramolecular disulfide (S-S) bonds that form during intracellular folding of the human chorionic gonadotropin (hCG)-beta subunit. Site-directed mutagenesis of every pair of Cys residues involved in the formation of each S-S bond was used to examine the roles that S-S bonds play in beta subunit folding and secretion. Tryptic maps of secreted hCG-beta showed that only one S-S bond formed in all S-S bond mutants that failed to fold from the earliest detectable beta folding intermediate, p beta 1, into a second major intermediate, p beta 2 (C34A-C88A, C38A-C57A or C9A-C90A mutants), whereas all 5 remaining S-S bonds formed in mutants when p beta 1-->p beta 2 conversion occurred (C23A-C72A, C93A-C100A, or C26A-C110A mutants). Nonreducing SDS-polyacrylamide gel electrophoresis showed that beta multimers were secreted from cells expressing S-S bond mutations where the folding of p beta 1-->p beta 2 was blocked. However, for mutations where p beta 1-->p beta 2 conversion was efficient, beta monomers rather than multimers were secreted. For all cell lines studied, secreted hCG-beta migrated as monomeric beta during reducing SDS-polyacrylamide gel electrophoresis, indicating that hCG-beta multimers formed via intermolecular cross-linking of unpaired thiols. Tryptic maps of hCG-beta isolated from mutants lacking the 34-88 bond, where > 80% turnover occurs, showed that only the 38-57 S-S bond formed. beta Subunits lacking the 9-90 linkage also have only S-S bond 38-57 formed, but < 10% turnover of C9A-C90A hCG-beta occurs. Thus, subtle conformational differences between partially folded or misfolded beta subunits may determine whether hCG-beta is degraded, or undergoes intracellular translocation and secretion.

Animals↗

PubMed1982

Monitoring therapy in trophoblastic diseases by radioimmunoassay of pregnancy-specific beta 1-glycoprotein and the beta subunit of human chorionic gonadotropin.

The beta-subunit of human chorionic gonadotrophin (hCG) and pregnancy-specific beta 1-glycoprotein (SP1) were measured simultaneously by specific radioimmunoassays in 473 serum samples from 43 patients with trophoblastic tumors. Both SP1 and hCG values were high in 16 untreated patients. 27 patients had been treated previously elsewhere, and their further treatment and monitoring were started simultaneously in our institute. Raised SP2 and hCG levels were found in 22 and 21 cases, respectively. Treatment was followed by a parallel decrease of both SP1 and hCG, but the hCG decline was more marked. Seronegativity was reached only after several months; SP1 was present in the serum for 60-150 days, and hCG could be found even after this time. Both parameters were sensitive indicators of residual tumor activity, calling for further therapy months before any clinical manifestation of recurrence. In three cases only one of the tumor makers could be found, which underlines the importance of the simultaneous measurement of hCG and SP1.

Choriocarcinoma↗

PubMed1988

Human chorionic gonadotropin beta-subunit in human semen.

The level of human seminal chorionic gonadotropin beta-subunit (hCG beta) was determined by radioimmunoassay (RIA). The mean hCG beta level in 34 normal men was 3.7 +/- 1.6 ng/ml, which was much higher than that in serum. The mean hCG beta level for 20 patients with mild oligozoospermia (20-39 x 10(6) sperm/ml) was 2.5 +/- 0.8 ng/ml, that for 34 patients with severe oligozoospermia (1-19 x 10(6) sperm/ml) was 1.7 +/- 0.5 ng/ml, and that for 21 azoospermia was 1.5 +/- 0.6 ng/ml. Thus, the decrease of sperm count was correlated with the decrease of hCG beta. In 17 cases to which testicular biopsy was applied together with sperm counting, the seminal hCG beta level was found to positively correlate with the germinal cell index (the ratio germinal cell count/Sertoli cell count) and with the testicular volume. The level of seminal hCG beta was also found to correlate negatively with the levels of seminal LH and FSH and positively with the level of seminal testosterone. These findings suggest that the production of seminal hCG beta is a process of spermatogenesis and closely related to spermatogenesis. The level of hCG beta in serum was too low to detect, and no relation to that in seminal plasma could be investigated. However, in 6 cases with testicular tumor, the hCG beta level in serum was high, whereas that in seminal plasma was rather low probably because of unilateral secretion. Enhanced production of hCG beta by tumor tissues and the destruction of the blood-testis barrier by proliferation of tumor cells seemed to be one of the causes of this high hCG beta level in serum. The hCG beta levels in 13 vasectomized seminal plasma and the prostatic fluid samples collected from 3 normal men were 1.5 ng/ml, which was similar to those in azoospermic patients. These findings suggest that the seminal hCG beta level consists of the hCG beta secreted by the testis and about 1.5 ng/ml of hCG beta from the prostate. Based on these results, seminal hCG beta is thought to be secreted by the prostate and the process of spermatogenesis and the value of seminal hCG beta may serve as an effective index for the testicular function.

Adult↗

PubMed1986

Formulation of a potential antipregnancy vaccine based on the beta-subunit of human chorionic gonadotropin (beta-hCG). IV. The role of adjuvants in booster injections.

Experiments were conducted in rabbits to determine the effect of adjuvant use on the antibody response following booster injections. The antigen used was in all cases the beta-subunit of human chorionic gonadotropin linked to tetanus toxoid (beta-hCG-TT). Adjuvants used were Al(OH)3, MDP analogs, and a streptococcus preparation, OK432. Primary vaccinations included Al(OH)3 adjuvant with or without supplementary adjuvants. In general, the greater the antibody response following primary vaccination, the greater the response following booster vaccination whether or not adjuvant was used in the booster. No increment in antibody titers was found by reason of including MDP analogs in booster vaccinations. OK432, in contrast, gave increased responses in booster injections which were in several cases statistically significant. The value of including Al(OH)3 in booster injections is not clear from the experimental data. In no case was the increment due to its inclusion large.

Adjuvants, Immunologic↗

PubMed1992

Kinetics of folding and assembly of the human chorionic gonadotropin beta subunit in transfected Chinese hamster ovary cells.

We have employed Chinese hamster ovary (CHO) cell lines transfected with either the wild type human chorionic gonadotropin beta (hCG-beta) gene alone (CHO beta cells) or in conjunction with the gene expressing the alpha subunit (CHO alpha,beta cells) to study the folding pathway of the hCG-beta subunit. In both CHO beta and CHO alpha,beta cells, the earliest detectable hCG-beta precursor, p beta 1, which had two of six potential disulfide bonds (34-88 and 38-57) formed, was converted to p beta 2, a form that, following the formation of disulfide bonds between cysteines 9-90 and 23-72, migrated more slowly than p beta 1 by sodium dodecyl sulfate-polyacrylamide gel electrophoresis under nonreducing conditions. The t1/2 for the conversion of p beta 1 to p beta 2 in CHO alpha,beta and CHO beta cells was 5 min, demonstrating that the alpha subunit had no effect on the rate of this conversion. Furthermore, the tryptic-releasable peptides generated from nonreduced p beta 1 or p beta 2 were the same in both CHO alpha,beta and CHO beta cells. Thus, both the rate and order of disulfide bond formation during the conversion of the folding intermediate p beta 1 into p beta 2 were the same whether or not the alpha subunit was present. A comparison between cell types expressing different alpha/beta subunit ratios revealed that the higher the glycoprotein hormone alpha subunit to beta subunit ratio, the greater the rate and extent of hCG heterodimer assembly.

Animals↗

PubMedDate not supplied

The biological and clinical significance of nicks in human chorionic gonadotropin and its free beta-subunit.

Human chorionic gonadotropin (hCG) is a glycoprotein hormone composed of two dissimilar subunits, alpha and beta. Nicks or missing peptide linkages have been found in the beta 44-52 region of the beta-subunit of hCG, whether from pregnancy or trophoblast disease. This article reviews recent reports about the location of nicks in hCG, their origin and occurrence, their effects on the steroidogenic and receptor-binding activities of hCG, and on the immunological activities of hCG and its free beta-subunit. Taken together, the reports show: (1) nicks occur primarily between beta 47 and beta 48, and to a lesser extent between beta 44 and beta 45; (2) the extent of nicking in hCG samples varies widely, from undetectable to 100 percent of molecules; (3) nicks greatly reduce the steroidogenic activity of hCG in vitro (nicked molecules have less than 20 percent of the activity of the intact hormone); (4) nicks may occur at the trophoblast-myometrial interface or in the circulation by the action of human leucocyte elastase or similar leucocytic protease; (5) hCG testing kits using dimer-specific antibodies may not detect nicked molecules and may give different results from those using other antibodies; (6) hCG international reference preparations and the CR series of hCG standards are variably nicked (10 percent to 20 percent), complicating the problem of discordant hCG results in nick-sensitive assays; (7) results from commonly used immunoassays for measurement of the hCG free beta-subunit vary by as much as tenfold because some of the antibodies employed do not detect nick free beta-subunit.

Amino Acid Sequence↗

PubMed1986

Purification and properties of a monoclonal antibody specific to the free beta-subunit of human chorionic gonadotropin (hCG beta) and its use in the isolation of free hCG beta produced by choriocarcinoma cells.

The free beta-subunit of hCG is secreted by several tumors and is reported to be different from native hCG beta. We have developed a monoclonal antibody, B158, specific for free hCG beta to facilitate the detection and isolation of tumor-derived free hCG beta in the presence of intact hCG and hCG alpha. B158 belongs to the immunoglobulin G1 subclass, has high affinity for hCG beta (Ka, 1.05 X 10(9) M-1), and can be obtained in large quantities. The sensitivity of this antibody to detect free hCG beta in a RIA is less than 1 ng. B158 has negligible cross-reactivity with hCG, human LH, and other intact glycoprotein hormones and reacts with the free beta-subunits of deglycosylated hCG, human LH, and ovine LH. The antibody completely inhibits the recombination of hCG beta with hCG alpha indicating the antigenic site to be in the subunit interaction region or its vicinity. Comparison of the amino acid sequences of the various cross-reacting and noncross-reacting hormones indicates that the antigenic site may be discontinuous and conformational. B158 was purified to homogeneity from ascites fluid by DEAE-Affi-Gel blue and hCG beta affinity chromatography. Immobilized pure B158 antibody was used to isolate free hCG beta in a homogeneous form and high yield from BeWo choriocarcinoma cell culture supernatants. This free hCG beta has a slightly higher mol wt than standard hCG beta and recombines normally with hCG alpha. BeWo cells appear to produce only one species of free hCG beta.

Animals↗

PubMed1987

Cosmid mapping of the human chorionic gonadotropin beta subunit genes by field-inversion gel electrophoresis.

A cosmid clone containing the entire hCG beta gene cluster has been isolated. The restriction map of this clone has been determined by an indirect-end-label FIGE (field inversion gel electrophoresis) method. Analysis of this cosmid clone shows that there are 6 hCG beta genes in human genomic DNA. A previously uncloned portion of the hCG beta cluster, termed the "gap" region, has been shown not to contain any sequences homologous to the hCG beta cDNA. The restriction mapping method employed in this study takes advantage of the superior resolution of FIGE for high molecular weight DNA fragments in the size range 15-50 kb. This method is broadly applicable and permits rapid and accurate restriction mapping for extended regions of genomic DNA that have been cloned into cosmid or lambda vectors.

Chorionic Gonadotropin↗