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PubMed1999

Identification of nuclear matrix and associated proteins that bind the haptoglobin gene cis-element.

To identify the major nuclear matrix proteins that bind to the rat haptoglobin gene cis-element, we isolated a soluble nuclear matrix protein fraction and analysed it by gel retardation. Two major DNA-binding proteins exhibiting different types of protein-DNA interactions were detected: a DNA sequence-specific 32-kDa isoform of transcription factor C/EBP beta, and a nuclear matrix protein p55 that bound to the DNA nonspecifically. During increased transcription of the haptoglobin gene in the course of the acute-phase reaction, the DNA-binding affinities and concentrations of these proteins in the soluble nuclear matrix fraction were increased. These data lend further evidence that the nuclear matrix is an active support structure that localizes gene regulatory proteins and participates in transcriptional regulation.

Acute-Phase Reaction↗
PubMed1993

Proteolytic cleavage of haptoglobin occurs in a subcompartment of the endoplasmic reticulum: evidence from membrane fusion in vitro.

The primary translation product of haptoglobin mRNA is a 45-kD polypeptide which is proteolytically cleaved shortly after its synthesis. Previous studies have indicated that the cleavage of this proform of haptoglobin occurs in the ER. In an attempt to characterize the cleaving enzyme, we found that upon incubation of microsomes from rat hepatocytes pulse labeled with [35S]methionine, little cleavage of labeled prohaptoglobin occurred. In contrast, when cells whose cytoplasmic proteins had been released by saponin treatment were incubated, 30-40% of the prohaptoglobin was cleaved. The addition of GTP caused a twofold stimulation, which was abolished by the nonhydrolyzable analog GTP gamma S. With a homogenate of the cells, the addition of GTP resulted in a fourfold stimulation of the degree of cleavage--from 15 to 60%. Differential centrifugation revealed that most of the cleaving activity resided in membranes sedimenting similarly to mitochondria and to a small fraction of the ER. These rapidly sedimenting membranes were therefore prepared from a rat liver homogenate. Upon treatment with high salt, light membranes were released which, when incubated with microsomes of pulse-labeled hepatocytes in the presence of detergent (and in the absence of GTP), induced specific cleavage of prohaptoglobin. The cleaving enzyme had an alkaline pH optimum indicating that it was not of lysosomal origin. These results suggest that cleavage of prohaptoglobin occurs in a subcompartment of the ER. Apparently, the connection between this compartment and the bulk of the ER is broken upon saponin treatment or homogenization but can be reestablished through a process requiring GTP hydrolysis.

Adenosine Triphosphate↗
PubMed1978

Acute phase reactants ceruloplasmin and haptoglobin and their relationship to plasma prostaglandins in rabbits bearing the VS2 carcinoma.

Results of previous studies have shown that the VX2 carcinoma in rabbits synthesizes large amounts of prostaglandin E2 (PGE2). PGE2 secreted by the tumor is rapidly metabolized and can be measured in plasma as the metabolite 13,14-dihydro-15-keto-PGE2 (PGE2-M). We have previously proposed that the hypercalcemia that occurs in rabbits bearing the VX2 carcinoma is due to excessive secretion of PGE2 by the tumor and its subsequent action on the skeleton as a bone resorption-stimulating factor. In the course of these studies, we noted that the plasma of rabbits bearing the VS2 carcinoma became blue about 1 wk after tumor implantation. The intensity of the color increased markedly thereafter. We therefore measured ceruloplasmin in plasma by both chemical and immunological assay methods. Plasma ceruloplasmin and PGE2-M rose in parallel (within 7-10 days) and preceded by 7-10 days the development of hypercalcemia. 2 wk after tumor implantation, plasma PGE2-M and ceruloplasmin had risen about 20- and 6-fold, respectively, while the rise in plasma calcium was just beginning. Indomethacin, an inhibitor of prostaglandin synthesis, given from the time of tumor implantation prevented completely the hypercalcemia and largely inhibited the rise in ceruloplasmin. When given after hyperprostaglandinemia had developed, indomethacin produced a fall in both PGE2-M and ceruloplasmin. A rise in plasma haptoglobin concentrations similar to that seen for ceruloplasmin was also observed. No changes in plasma albumin concentrations occurred. We conclude that the acute phase reactants ceruloplasmin and haptoglobin rise rapidly in the plasma of rabbits bearing the VX2 carcinoma, and that this increase is related to arachidonic acid metabolism in these animals. It is possible that arachidonic acid metabolites also play a role in the elevations of these two plasma proteins observed in certain patients with malignant tumors.

Animals↗
PubMed2000

Haptoglobin polymorphism in human immunodeficiency virus infection: Hp0 phenotype limits depletion of CD4 cell counts in HIV-1-seropositive individuals.

Patients seropositive for human immunodeficiency virus (HIV) type 1 and seronegative control subjects were categorized by their haptoglobin phenotypes, which were determined by electrophoresis of hemoglobin-supplemented plasma samples followed by benzidine staining. The CD4 cell counts, determined by flow cytometry from peripheral blood mononuclear cells according to subject categories, were severely diminished in seropositive patients with the Hp2-2 phenotype (P<.025). In contrast, the CD4 cell counts for patients with the Hp0 phenotype remained relatively high (P<.025), compared with those of the controls. In seronegative patients, CD4 cell counts were generally high (P<.005), but they were more elevated in subjects with Hp2-2 and Hp1-1, although the differences were not significant. Thus, the Hp2-2 phenotype is associated with poor outcome in HIV-1 infection, whereas the Hp0 phenotype is associated with a better prognosis once the patient is infected with HIV-1. Haptoglobin polymorphism plays a significant role in HIV-1 infection and transmission.

Adult↗
PubMed1986

Expression of cloned human haptoglobin and alpha 1-antitrypsin complementary DNAs in Saccharomyces cerevisiae.

Nucleotide sequences coding either for human preprohaptoglobin or for prohaptoglobin have been placed under the control of yeast ARG3 expression signals. Recombinant plasmids pRIT12598 and pRIT12597 express the prepro- and the pro-form of alpha 2 beta haptoglobin respectively, but at very low levels. Comparison with the expression of human pre- and mature alpha 1-antitrypsin cDNAs, cloned in the same expression vector, reveals large differences in the levels of specific proteins produced in yeast, although specific mRNA levels are similar. It is shown that presence or absence of the signal sequence in the cDNA construction results in a 20- to 30-fold difference in the yields of heterologous products. However, since haptoglobin and alpha 1-antitrypsin behave differently, the difference in expression for prohaptoglobin compared with the expression of mature alpha 1-antitrypsin is about three orders of magnitude. In addition, we provide evidence that glycosylation of both proteins can occur in yeast only when the signal sequence is present in the DNA constructions.

DNA↗
PubMed1996

Transcriptionally active haptoglobin-related (Hpr) gene in hepatoma G2 and leukemia molt-4 cells.

The aim of the present study was to answer the question: Is the haptoglobin-related (Hpr) gene expressed in tumor cells? Our strategy of cloning the cDNA was to screen a human hepatoma G2 cDNA expression library in lambda gt11 using three different probes complementary to the coding strands of regions of the Hpr gene that contain codon changes permitting a discrimination from haptoglobin gene Hp1F. Among 8 x 10(5) recombinant phages screened, 2 hybridized to all three probes under stringent conditions. A 1.5 kb cDNA designated ST-1 was subcloned and sequenced. Almost total identity was found with the Hpr predicted exons 2-5, although exon 1 was missing. The ST-1 partial cDNA clone was used as a probe to screen a human leukemia molt-4 cDNA expression library in lambda gt11. Among 10(6) recombinant phages screened, 1 hybridized under stringent conditions. A 1.5 kb cDNA designated ST-2 was subcloned and sequenced. ST-1 and ST-2 cDNA were identical except for an insert of A at position 500 of ST-1 cDNA. Two different nucleotide changes were observed in the ST-1 and ST-2 sequences as compared with the expected Hpr cDNA sequence. An alternative processing of Hpr pre-mRNA was found in both cDNA clones that included 126 bp of the 3'-region of intron 1. This intronic sequence is thereby retained in the mature mRNA. cDNA analysis revealed an in-frame ATG in intron 1. Transcription/translation assay was used to demonstrate that the Hpr message could be translated from the internal methionine codon. We have thus shown for the first time that the Hpr gene is expressed in the human hepatoma G2 and leukemia molt-4 cell lines.

Amino Acid Sequence↗
PubMed1984

Evolution of haptoglobin: comparison of complementary DNA encoding Hp alpha 1S and Hp alpha 2FS.

Haptoglobin is a transport glycoprotein which removes free hemoglobin from the circulation of vertebrates. In human populations haptoglobin is polymorphic due to three alleles, Hp alpha 1F, Hp alpha 1S and Hp alpha 2. The Hp alpha 2 allele is roughly twice the length of the Hp alpha 1 alleles and is the product of a partial gene duplication possibly resulting from an unequal crossover event in a heterozygous genotype Hp alpha 1F/Hp alpha 1S. In the study described here we compare the cDNA encoding Hp alpha 1S to that encoding Hp alpha 2FS . Both have a leader sequence followed by the genotypic alpha chain sequence, a beta sequence and an untranslated sequence in the 3' end. The cDNA encoding Hp alpha 2FS is composed of alpha 1F and alpha 1S domains differing by four nucleotide replacements. Hp alpha 1S cDNA contains the same replacement site mutations found in the alpha 1S domain of Hp alpha 2FS , indicating that this coding region has sustained few, if any, mutations since its incorporation into the Hp alpha 2FS gene.

Alleles↗
PubMed1975

Proteolytic degradation of hemoglobin-haptoglobin complex by lysosomal enzymes from rat liver.

The catabolic degradation of hemoglobin and of its complex with haptoglobin by lysosomal enzymes from rat liver was studied with special emphasis on the action of cathepsins D and E. The digestion of free hemoglobin can be mainly attributed to the action of cathepsin D [EC 3.4.23.5], while the digestion of the complex in the pH rand 2-3 is due more to the action of cathepsin E than that of cathepsin D. The enzymic activities of both cathepsins were strongly inhibited by pepstatin, and 4M urea inactivated cathepsin E. Measurements of the peroxidase activity and optical rotatory dispersion of the hemoglobin-haptoglobin complex showed that the complex suffered rapid denaturation below pH 2.9.

Animals↗
PubMed2003

Iron, haptoglobin phenotype, and HIV-1 viral load: a cross-sectional study among pregnant Zimbabwean women.

BACKGROUND: Viral load is a determinant of HIV-1 progression and transmission. Iron status and the phenotype of haptoglobin, a heme-binding acute phase reactant, may be determinants of viral load. We aimed to describe the effect of iron status, haptoglobin phenotype (Hp), and other predictors on HIV-1 viral load. METHODS: Based on a cross-sectional study among 1669 antenatal care attenders (22-35 weeks) in Zimbabwe, 526 (31.5%) were found to be HIV infected. The role of season, age, gravidity, gestational age, malaria parasitemia, Hp, and elevated serum alpha(1)-antichymotrypsin (ACT) as well as serum ferritin, folate, retinol, and beta-carotene on HIV viral load among the 526 HIV-infected women was assessed using multiple linear regression analysis. RESULTS: The distribution of Hp 1-1 (32%), Hp 2-1 (48%), and Hp 2-2 (20%) was not different from that of 53 uninfected women. Mean viral load was 3.85 log(10) (95% CI: 3.77-3.93) genome equivalents (geq)/mL, ranging from 3.77 (95% CI: 3.64-3.90) geq/mL in women with Hp 1-1 to 4.05 (95% CI: 3.81-4.21) geq/mL in women with Hp 2-2. With elevated serum ACT controlled for, women with Hp 2-2 had viral loads twice (95% CI: 1.4-4.0, p =.002) that of women with Hp 1-1, whereas those with serum ferritin <6 micro g/L had viral loads less than one third (95% CI: 0.13-0.53, p =.013) that of women with serum ferritin >24 micro g/L. Viral loads were also higher in women enrolled in the early rainy season compared with the dry season, in gravidae 4+ compared with gravidae 1 through 3, and in those with moderately elevated compared with low serum alpha(1)-antichymotrypsin, but neither age, gestational age, serum folate, serum retinol, nor serum beta-carotene were predictors. CONCLUSION: Storage iron, Hp 2-2, and elevated ACT are independent positive predictors of HIV-1 viral load. The positive relationship between serum ferritin and viral load was not the result of an acute phase response or iron accumulation with advanced HIV infection. A possible detrimental role of iron in HIV infection would have serious public health implications.

Female↗
PubMed1990

Serum protein markers in Chinese schizophrenics--haptoglobin types and transferrin and group-specific component subtypes.

Four hundred and thirty-nine Chinese schizophrenic male patients were investigated for the distribution of haptoglobin types; transferrin and group-specific component subtypes. The allelic frequencies of these three polymorphisms in the patient group were compared with those in healthy controls from published series. An excess of Gc2 over Gc1 (chi 2(1) 4.1; P less than 0.05) as well as a lack of Gc1S (chi 2(1) 15.3; P less than 0.001) was observed in schizophrenia. The relative risks of Gc1F, Gc1S and Gc2 have been estimated as 1.12, 0.76 and 1.15, respectively. It appears from this study that the presence of Gc2 renders individuals susceptible while Gc1S offers protection for schizophrenia. No such association was found for the haptoglobin or transferrin polymorphisms.

Blood Proteins↗
PubMed1975

C3, GBG, orosomucoid and haptoglobin polymorphisms. Improved staining methods.

C3, GBG, and orosomucoid polymorphisms were electrophoresed in a high-voltage agarose method which permitted the typing of 15-20 samples. The increased sensitivity of the dye Coommassie blue was used to stain the protein, and yielded higher resolution than amido black. The typing of haptoglobin samples, was facilitated by devising a method which utilizes the peroxidase activity of the haptoglobin-hemoglobin complex with 90-tolidine and hydrogen peroxide as substrates and 4-chloro-1-naphthol as coupler.

Complement System Proteins↗
PubMed1989

Antiserum to pregnancy-associated plasma protein A (PAPP-A) recognizes human haptoglobin.

The presence of pregnancy-associated plasma protein A (PAPP-A) in non-pregnancy serum has been questioned with reference to insufficient specificity of the antibodies raised against this glycoprotein in some departments and used in immunoassay. For convenience, but also because of this unclear situation, many laboratories now use the only commercially available anti-PAPP-A preparations in their assays. By analysing pregnancy and non-pregnancy serum with two-dimensional electrophoresis (2-DE) and Western blotting, we could demonstrate that this antiserum marketed by Dakopatts (Denmark) was capable of binding haptoglobin whereas our own (Dr P. Bischof) antibody preparation did not recognize haptoglobin.

Antibodies, Monoclonal↗
PubMed2006

Utilization of myoglobin as a heme source by Haemophilus influenzae requires binding of myoglobin to haptoglobin.

Haemophilus influenzae has an absolute growth requirement for heme. One potential in vivo source of heme is the protein myoglobin which is found at low levels in human serum. No tested H. influenzae strain was able to use myoglobin as a heme source. However, all strains were able to utilize the heme from myoglobin when myoglobin was complexed with haptoglobin. Utilization of the haptoglobin-myoglobin complex was shown to be mediated by the previously described hemoglobin/hemoglobin-haptoglobin-binding proteins of H. influenzae.

Bacterial Proteins↗
PubMed1984

C3 and haptoglobin polymorphism in dementia of the Alzheimer type.

The C3 and haptoglobin phenotype distribution was studied in 60 patients with dementia of the Alzheimer type. In contrast with earlier reports we did not find any significant association between dementia of the Alzheimer type and certain C3 or haptoglobin phenotypes.

Aged↗
PubMed1990

Serum haptoglobin types in patients with hemoglobinopathies.

Haptoglobin types were determined in 626 individuals living in the State of São Paulo (Brazil). Of these, 484 had Hb AA, 31 major beta thalassemia, 43 minor beta thalassemia, 14 Hb SS, and 54 Hb AS. Frequency distribution of the three most common types observed among patients with type beta thalassemia differed significantly from that observed in the Caucasian group with Hb AA. There was a significant increase in Hp 1-1, which led us to assume that these disorders participate in a selective process acting on haptoglobins and altering the equilibrium of their frequencies. This relationship was not observed when we compared patients with Hb SS and Hb AS with Black patients with Hb AA, although the type most often observed among patients with Hb SS was Hp 1-1. The distributions of Hp groups observed among Caucasian and Black patients with Hb AA were similar to those obtained by other investigators for the South and Southeast regions of Brazil, with the exception of Rio de Janeiro.

Alleles↗
PubMed1983

Sequential determination of CRP, alpha 1-antitrypsin and haptoglobin in neonatal septicaemia.

In 312 preterm and term newborn infants serum concentrations of C-reactive protein (CRP), haptoglobin and alpha 1-antitrypsin were measured during several days by radial immunodiffusion. In addition white blood cell count and the ratio of band to total neutrophils (B/N-ratio) were determined. In 12 infants with proven sepsis CRP was found elevated above the upper limit of the normal range (20 mg/l). Successful therapy was followed by a decrease of CRP concentration. In infants with suspected infection high CRP values were found in most cases. In contrast, haptoglobin and alpha 1-antitrypsin concentrations differed not significantly between the group of infants without infection, with proven and with suspected infection. White blood cell count and B/N-ratio also were not appropriate for the early identification of bacterial infection in the newborn period.

C-Reactive Protein↗
PubMed1967

Ring D chromosome: a second case associated with anomalous haptoglobin inheritance.

A second child with a ring D chromosome and anomalous inheritance of haptoglobin has been identified. Autoradiographic studies of peripheral lymphocytes from this child and of those from the previously described patient indicate that the ring in each is derived from chromosome No. 13. These findings are evidence that the locus for the haptoglobin alpha-chain is situated on one end of chromosome No. 13.

Autoradiography↗
PubMed1995

Killing of trypanosomes by the human haptoglobin-related protein.

African trypanosomes cause disease in humans and animals. Trypanosoma brucei brucei affects cattle but not humans because of its sensitivity to a subclass of human high density lipoproteins (HDLs) called trypanosome lytic factor (TLF). TLF contains two apolipoproteins that are sufficient to cause lysis of T. b. brucei in vitro. These proteins were identified as the human haptoglobin-related protein and paraoxonase-arylesterase. An antibody to haptoglobin inhibited TLF activity. TLF was shown to exhibit peroxidase activity and to be inhibited by catalase. These results suggest that TLF kills trypanosomes by oxidative damage initiated by its peroxidase activity.

Amino Acid Sequence↗