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PubMed2001

The use of in vitro fertilization techniques to investigate the fertilizing ability of bovine sperm with proximal cytoplasmic droplets.

The objective of this experiment was to determine the effect of proximal droplets on sperm-oocyte binding, zona penetration, fertilization, and the developmental competence of oocytes fertilized by sperm with proximal droplets (PD) in an in vitro fertilization (IVF) and culture system. Frozen semen from three bulls (PD1, PD2 and PD3) with varying proportions of normal appearing sperm with proximal droplets and semen from a normal control bull (C) were used in this experiment. The mean number of sperm bound to the zona pellucida (26.8 +/- 2.0, n=100; 15.2 +/- 1.1, n=100; 16.2 +/- 1.0, n=100) for bulls PD1, PD2, and PD3, respectively, were significantly lower (P<0.05) than that of the control bull C (47.4+/- 1.9; n=114). No spermatozoa with PD were found bound to the zona pellucida and this finding was consistent among the three bulls. The percentage penetration of zonae for the bulls PD1, PD2 and PD3 (74%, 74/100; 71%, 71/100 and 69%, 69/100, respectively) were not different than that of bull C (72%, 179/245). Similarly, the mean number of sperm penetrating the zona pellucida (1.43+/- 1.2, 1.24 +/- 1.1 and 1.20 +/- 1.1, for bulls PD1, PD2 and PD3, respectively) were not different than that of bull C (1.45 +/- 1.1). However, fertilization rates (8.8%, 8/90; 16.8%, 16/95; and 10.6%, 11/103, for bulls PD1, PD2 and PD3, respectively) were lower (P<0.001) than that of bull C (68.7%; 77/112). Similarly, cleavage rates (5%, 10/200; 8%, 8/100 and 14%, 15/111) for the bulls PD1, PD2 and PD3, respectively, were lower than that of the control bull, C (60.7%; 79/130). Cleaved zygotes resulting from the fertilization of oocytes by apparently normal sperm from bulls with PD did not develop beyond cleavage, whereas, 43.8% (57/130) morulae and 20% (26/130) blastocysts were produced by oocytes fertilized by sperm from bull C. In summary, normal appearing sperm with PD did not bind to the zona pellucida. Apparently normal sperm with out proximal droplets co-existing in the semen along with sperm containing PD were also functionally deficient, resulting in reduced zonae binding and zygotes resulting from insemination with semen with a high percentage of PD did not develop beyond cleavage.

Animals↗
PubMed2000

Overexpression and characterization of carboxyl-terminal processing protease for precursor D1 protein: regulation of enzyme-substrate interaction by molecular environments.

CtpA, which is classified as a novel type of serine protease with a Ser/Lys catalytic dyad, is responsible for the C-terminal processing of precursor D1 protein (pD1) of the photosystem II reaction center, a process that is indispensable for the integration of water-splitting machinery in photosynthesis. In this study, overexpression in Escherichia coli and one-step purification of spinach CtpA were carried out to analyze the characteristics of this new type of protease and to elucidate the molecular interactions in the C-terminal processing of pD1 on the thylakoid membrane. The successful accumulation of functional CtpA in E. coli may argue against the possibility, based on homology to E. coli Tsp, that the enzyme is involved in the degradation of incomplete proteins in chloroplasts, e.g. by utilizing the ssrA-tagging system. Analysis using a synthetic pD1 oligopeptide demonstrated that the enzymatic properties (including substrate recognition) of overexpressed CtpA with an extra sequence of GSHMLE at the N terminus were indistinguishable from those of the native enzyme. CtpA was insensitive to penem, which has been shown to inhibit some Ser/Lys-type proteases, suggesting that the catalytic center of CtpA is quite unique. By using the substrate in different molecular environments (i.e. synthetic pD1 oligopeptide in solution and pD1 in photosystem II-enriched thylakoid membrane), we observed a dramatic difference in the pH profile and affinity for the substrate, suggesting the presence of a specific interaction of CtpA with a factor(s) that modulates the pH dependence of proteolytic action in response to physiological conditions.

Amino Acid Sequence↗
PubMed1994

Gastrointestinal effects and energy value of polydextrose in healthy nonobese men.

We studied seven healthy volunteers before and during acute (PD1) and chronic (PD2) ingestion of 30 g polydextrose (PD)/d. The energy value of PD was assessed after [U-14C]PD was added to the 10-g morning dose of PD during PD1 and at the end of PD2. Thirty-one +/- five percent (mean +/- SD) (PD1) and 29 +/- 4% (PD2) of the dose appeared in breath within 48 h. A small fraction of the ingested radioactivity was recovered in urine (4 +/- 1%) and excreted in flatus (< or = 1%) and in feces as volatile fatty acids (VFAs) (< 1%) and bacteria (3-4%); the remaining radioactivity in stools, 33 +/- 3% (PD1) and 32 +/- 4% (PD2), was assumed to be intact PD. Breath excretion of the label was 49 +/- 5% after intracolonic infusion of [U-14C] acetate. The energy value of PD, calculated by means of Miller and Wolin's stoichiometric equation of colonic fermentation, was similar during PD1 and PD2: 4.0 and 6.1 kJ/g, respectively, when breath 14CO2 and VFA production from PD were used for calculation.

Adult↗
PubMed2006

G-protein-coupled receptor 1, G-protein Galpha-subunit 1, and prephenate dehydratase 1 are required for blue light-induced production of phenylalanine in etiolated Arabidopsis.

Different classes of plant hormones and different wavelengths of light act through specific signal transduction mechanisms to coordinate higher plant development. A specific prephenate dehydratase protein (PD1) was discovered to have a strong interaction with the sole canonical G-protein Galpha-subunit (GPA1) in Arabidopsis (Arabidopsis thaliana). PD1 is a protein located in the cytosol, present in etiolated seedlings, with a specific role in blue light-mediated synthesis of phenylpyruvate and subsequently of phenylalanine (Phe). Insertion mutagenesis confirms that GPA1 and the sole canonical G-protein-coupled receptor (GCR1) in Arabidopsis also have a role in this blue light-mediated event. In vitro analyses indicate that the increase in PD1 activity is the direct and specific consequence of its interaction with activated GPA1. Because of their shared role in the light-mediated synthesis of phenylpyruvate and Phe, because they are iteratively interactive, and because activated GPA1 is directly responsible for the activation of PD1; GCR1, GPA1, and PD1 form all of or part of a signal transduction mechanism responsible for the light-mediated synthesis of phenylpyruvate, Phe, and those metabolites that derive from that Phe. Data are also presented to confirm that abscisic acid can act through the same pathway. An additional outcome of the work is the confirmation that phenylpyruvate acts as the intermediate in the synthesis of Phe in etiolated plants, as it commonly does in bacteria and fungi.

Amino Acid Sequence↗
PubMed2002

In utero ethanol suppresses cerebellar activator protein-1 and nuclear factor-kappa B transcriptional activation in a rat fetal alcohol syndrome model.

A model of fetal alcohol syndrome was used to investigate prenatal ethanol effects on cerebellar transcription factors. Pregnant Sprague-Dawley rats were divided into three treatment groups: ethanol-exposed (E), calorically matched pair-fed (PF), and freely fed ad libitum (AL) groups. Ethanol exposure was stopped 2 days before parturition. The DNA binding in neonatal cerebella of the redox-sensitive transcription factors nuclear factor-kappa B (NF-kappa B) and activator protein-1 (AP-1) were determined by electrophoretic mobility shift assays. On the first postnatal day (PD1), there was decreased activation of these transcription factors in the E group relative to the control groups. The PD1 transcriptional effects were reversed as the neonate underwent development without further ethanol exposure. Western blot studies showed no corresponding decreases in protein amounts of both AP-1 and NF-kappa B components on PD1. Postnatal glutathione levels and catalase activity, as measures of oxidative stress hypothesized to be a probable cause of the transcriptional effects, showed no statistically significant effects attributable to ethanol. Examination of prenatal cerebella on embryonic day 20 (EM20), a time during ethanol exposure, showed DNA-binding trends similar to those of PD1. EM20 Western blot studies showed decreases in the levels of the active form of glycogen synthase kinase-3 (GSK-3). GSK-3 inhibition was reversed by PD1. Blocking of GSK-3 activity with gestational dietary lithium diminished both AP-1 and NF-kappa B DNA binding. Thus, prenatal ethanol exposure has the effect of diminishing pro-survival transcriptional activation, an effect possibly mediated by changes in GSK-3 activity.

Animals↗
PubMed1990

Postnatal development of the electrical activity of rat nigrostriatal dopaminergic neurons.

Extra- and intracellular recordings were obtained in vivo from dopaminergic nigrostriatal neurons in rat pups ranging in age from postnatal day (PD) 1 to PD28, and in adult rats. Neurons from PD1-3 rats were active at very low rates in a random pattern, rarely showed bursting activity, and often exhibited long periods of up to several minutes of silence. Spontaneous spikes were of relatively low amplitude and long duration. The mean firing rate increased and became more regular over time, and short bursts consisting of only 2 spikes were observed. By the second postnatal week, the initial segment component of the spontaneous spike resembled that seen in adults, but the somadendritic component was still relatively small, and there was often a very marked temporal delay between the two. Near the end of the second postnatal week, neurons exhibited a transient phase of pacemaker-like activity. Mean firing rates continued to increase with time, as did the incidence and complexity of bursting activity. The spontaneous firing rate, pattern and spike morphology approached adult values by the fourth postnatal week. Antidromic responses from neostriatum were obtained as early as PD1, and consisted of a significantly greater proportion of full initial segment-soma dendritic spikes compared to nigrostriatal neurons from adult rats. There was usually a long delay between the initial segment and somadendritic components of the spike. Mean antidromic latency and mean antidromic threshold did not vary significantly from PD1-3 to adults. Axonal conduction velocity reached maximal adult values by PD16-21. Neostriatal-evoked orthodromic responses consisted principally of a poststimulus inhibition whose duration decreased from PD1 through adulthood. Pure excitatory responses were very rarely observed at any age. Intracellular recordings from PD2, PD3 and PD5 rats revealed striatal-evoked inhibitory postsynaptic potentials in non-dopaminergic nigral neurons with a mean onset latency (9.8 +/- 3.8 ms) which did not differ from that previously reported for adult rats.

Action Potentials↗
PubMed1995

Recognition of the structure around the site of cleavage by the carboxyl-terminal processing protease for D1 precursor protein of the photosystem II reaction center.

In order to analyze the structural requirement(s) for proteolytic cleavage, synthetic oligopeptides corresponding to the carboxyl-terminal (COOH-terminal) sequence of the precursor to the D1 protein (pD1) of the photosystem II reaction center, with or without substituted side chain(s) around the cleavage site, were subjected to enzymatic analysis with partially purified processing protease from spinach. The efficiency of action as a competitive inhibitor of the enzymatic cleavage of the COOH-terminal extension, as well as the capacity to serve as a substrate, was used as an indication of effective binding to the protease. Neither a COOH-terminal fragment consisting of the 9 amino acids that are cleaved from pD1 by the protease nor a COOH-terminal fragment of the mature protein consisting of 15 amino acids inhibited the enzymatic processing of pD1. By contrast, a COOH-terminal fragment of pD1 consisting of 24 amino acids, which included the sequences of both the COOH-terminal extension and the COOH-terminal 15 amino acids of the mature protein, was effective both as a competitive inhibitor and as a substrate. This result suggests that the structure formed by linkage between these two parts of the protein moiety is important in the substrate-enzyme interaction. Among substitutions around the cleavage site, the replacement of Leu-343 by Ala (L343A) specifically destroyed the ability of the oligopeptide to serve as either a substrate or an inhibitor, suggesting that the presence of the hydrophobic Leu residue is crucial for the formation of the recognition site. A series of six substitutions at Ala-345 had marked effects on the value of Vmax, without affecting the binding affinity, as represented by Km; the order of substitutions at residue 345 in terms of their effects on Vmax was Ala,Ser,Phe,Cys > Gly > Val >> Pro. With a Pro residue at position 345, the oligopeptide was practically inactive as a substrate.

Amino Acid Sequence↗
PubMed1988

Identification of negative and positive regulatory elements associated with a class I major histocompatibility complex gene.

Regulatory DNA sequence elements were functionally identified in the 5'-flanking region of a gene, PD1, which encodes a porcine classical transplantation antigen. Both a positive regulatory element and a novel negative regulatory DNA element were mapped within 1.1 kilobases upstream of exon 1. The negative regulatory element reduced the activity of both the homologous PD1 promoter and a heterologous simian virus 40 promoter. In vivo competition experiments indicated that the functions of the PD1 positive and negative regulatory elements are mediated by distinct cellular trans-acting factors. The PD1 positive regulatory element interacted with cellular factors in common with those binding to the simian virus 40 enhancer. Finally, the negative regulatory element required the presence of a positive regulatory element to function. This interaction between positive and negative regulatory elements represents a novel mechanism for regulating gene expression.

Amino Acid Sequence↗
PubMed2006

Resolvin D series and protectin D1 mitigate acute kidney injury.

Omega-3 fatty acid docosahexaenoic acid is converted to potent resolvins (Rv) and protectin D1 (PD1), two newly identified families of natural mediators of resolution of inflammation. We report that, in response to bilateral ischemia/reperfusion injury, mouse kidneys produce D series resolvins (RvDs) and PD1. Administration of RvDs or PD1 to mice before the ischemia resulted in a reduction in functional and morphological kidney injury. Initiation of RvDs and RvD1 administration 10 min after reperfusion also resulted in protection of the kidney as measured by serum creatinine 24 and 48 h later. Interstitial fibrosis after ischemia/reperfusion was reduced in mice treated with RvDs. Both RvDs and PD1 reduced the number of infiltrating leukocytes and blocked TLR-mediated activation of macrophages. Thus, the renal production of Rv and protectins, a previously unrecognized endogenous anti-inflammatory response, may play an important role in protection against and resolution of acute kidney injury. These data may also have therapeutic implications for potentiation of recovery from acute kidney injury.

Acute Disease↗
PubMed1990

Light-dependent D1 protein synthesis and translocation is regulated by reaction center II. Reaction center II serves as an acceptor for the D1 precursor.

Light induces an irreversible modification of the photosystem II reaction center (RCII) affecting specifically one of its major components, the D1 protein (Ohad, I., Adir, N., Koike, H., Kyle, D. J., and Inoue, Y. I. (1990) J. Biol. Chem. 265, 1972-1979) which is degraded and replaced continuously (turnover). The turnover rate of D1 is related to light intensity. Evidence is presented showing that RCII translocates from the site of damage in the grana (appressed) domain of the chloroplast membranes to unappressed membrane domains where the D1 precursor protein (pD1) is translated and becomes integrated into RCII. Several forms of RCII (a, a*, and b) were identified on the basis of their electrophoretic mobility. pD1 was found only in the a and b forms in the unappressed membranes. Processing of pD1 occurs after its integration into RCII. Mature D1 appeared mostly in the a form of RCII and following its translocation to the appressed membrane domains also in the a* form. Thus the light intensity-dependent synthesis of D1 protein is related to the availability of modified RCII which serves as an acceptor for pD1. The shuttling of RCII between the two membrane domains may represent a control mechanism of thylakoid membrane protein synthesis.

Biological Transport↗
PubMed1998

Effects of recycled paper dust extracts on isolated guinea pig trachea.

The effect of paper dust collected at two different locations in a paper recycling plant (PD1 and PD2) on isolated nonsensitized guinea pig tracheal smooth muscle was studied in vitro. Dust extracts were prepared as a 1:10 w/v aqueous solution. Dose-related contractions of guinea pig tracheal rings were elicited with both PD1 and PD2. Pharmacologic studies were performed with atropine (10(-6) M), indometacin (10(-6) M), pyrilamine (10(-6) M), LY171883 (10(-5) M), nordihydroguaiaretic acid (10(-5) M), and TMB8 (10(-5) M). The possible role of endogenous neuropeptides in this constrictor process was studied by depleting neural mediators with capsaicin (5 x 10(-6) M) before challenge with dust extracts. Constrictor effects were partially inhibited by a wide variety of the mediator blocking agents. The effects of both extracts were almost totally inhibited by the anticholinergic agent atropine, suggesting that a principal pathway mediating this response may involve the parasympathetic nervous system. The intracellular calcium-blocking agent TMB8 also induced a reduction of the contractile responses to PD1 and PD2 consistent with the well established role of intracellular calcium in smooth muscle constriction. Pretreatment with capsaicin significantly increased the contractile activity of paper dust extracts but only at the higher doses of these extracts. This suggests that the effect of paper dust is not initiated by the release of mediators stored in sensory nerves but that the prerelease of these mediators may enhance the constrictor effects of these dusts. We suggest that paper dust extracts cause dose-related airway smooth muscle constriction possibly associated with the release of cholinergic as well as other mediators. The constrictor effect does not require tissue presensitization or the release of neuropeptides from sensory nerves.

Animals↗
PubMed1999

Specific detection of Xylella fastidiosa Pierce's disease strains.

Pierce's disease (PD, Xylella fastidiosa) of grapevine is the primary pathogen limiting vinifera grape production in Florida and other regions of the southeastern United States. Quick and accurate detection of PD strains is essential for PD studies and control. A unique random amplified polymorphic DNA (PD1-1-2) was isolated from a PD strain from Florida. Fragment PD1-1-2 was cloned, sequenced, and found to be 1005 bp in length. PCR primers were designed to utilize these sequence data for PD strain detection. One primer set (XF176f-XF954r) amplified a 779-bp DNA fragment from 34 PD strains including seven pathotypes of X. fastidiosa, but not from strains of Xanthomonas campestris pv. campestris, Xan. vesicatoria or Escherichia coli. A second primer set (XF176f and XF686r) amplified a 511-bp fragment specific to 98 PD strains, but not from strains of citrus variegated chlorosis, mulberry leaf scorch, oak leaf scorch, periwinkle wilt, phony peach, or plum leaf scald. Sequence analysis indicated that RAPD fragment PD1-1-2 contains a Ser-tRNA gene. The PD-specific region includes a TaqI restriction site (TCGA) and is 150 bp downstream of the Ser-tRNA gene.

Base Sequence↗
PubMed1996

Functional renal maturation in rat neonates after prenatal exposure to furosemide.

We investigated the pattern of functional renal maturation and electrolyte handling on postnatal day 1, (PD1), day 5 (PD5), and day 12 (PD12) in rat neonates, after mothers were given furosemide during pregnancy. The drug was administered (75 mg/kg per day i.p.) on day 7-11 (organogenesis) and 14-18 (nephrogenesis) of gestation. On PD1 and PD5, there was a disturbance of the urinary concentrating ability with a hyperdiuresis and an over-stimulated ionic exchange, mainly the distal sodium reabsorption. From PD1 to PD12, a progressive functional recovery in electrolyte handling appeared. However, on PD12, when nephrogenesis was achieved, the renal concentrating defect remained. We discuss the possibility of a drug-induced delay in the development of the loop of Henle, leading to functional and morphological adaptations of already developed parts of the nephron.

Animals↗
PubMed1987

Structure and expression of class I MHC genes in the miniature swine.

The genome of the miniature swine, unlike other species, contains a relatively small class I MHC gene family, consisting of only seven members. This provides an excellent system in which to identify and characterize the regulatory mechanisms which operate to both coordinately and differentially regulate the expression of a multi-gene family. The structure of class I SLA genes, like other class I genes, consists of eight exons encoding a leader sequence, three extracytoplasmic domains, a transmembrane domain and intracytoplasmic domains. Despite the common structure, two sub-families of class I genes can be distinguished within the SLA family. One, containing the closely related PD1 and PD14 genes, encodes the classical transplantation antigens. Another contains the highly divergent PD6; the functions of the products of this subfamily, if any, are not known. The class I SLA genes share some common regulatory mechanisms, as evidenced by the fact that all three genes analyzed are transcribed in mouse L cells. Furthermore, interferon treatment of transfected mouse L cells enhances expression of all three genes. Both PD1 and PD6 are transcribed in vivo, where the highest levels of expression are observed in lymphoid tissues. Superimposed on the common patterns of class I gene expression are distinct ones, as evidenced by the findings that PD1 is preferentially expressed in B cells, whereas PD6 is preferentially expressed in T cells. These differences may reflect the extensive divergence of the 5' flanking sequences of these genes. Future studies will be aimed at elucidating the precise molecular interactions and mechanisms which give rise to the observed differential expression.

Animals↗
PubMed2006

Resolvin D1, protectin D1, and related docosahexaenoic acid-derived products: Analysis via electrospray/low energy tandem mass spectrometry based on spectra and fragmentation mechanisms.

Resolvin D1 (RvD1) and protectin D1 (Neuroprotectin D1, PD1/NPD1) are newly identified anti-inflammatory lipid mediators biosynthesized from docosahexaenoic acid (DHA). In this report, the spectra-structure correlations and fragmentation mechanisms were studied using electrospray low-energy collision-induced dissociation tandem mass spectrometry (MS/MS) for biogenic RvD1 and PD1, as well as mono-hydroxy-DHA and related hydroperoxy-DHA. The loss of H2O and CO2 in the spectra indicates the number of functional group(s). Chain-cut ions are the signature of the positions and numbers of functional groups and double bonds. The observed chain-cut ion is equivalent to a hypothetical homolytic-segment (cc, cm, mc, or mm) with addition or extraction of up to 2 protons (H). The alpha-cleavage ions are equivalent to: [cc + H], with H from the hydroxyl through a beta-ene or gamma-ene rearrangement; [cm - 2H], with 2H from hydroxyls of PD1 through a gamma-ene rearrangement, or 1H from the hydroxyl and the other H from the alpha-carbon of mono-HDHA through an alpha-H-beta-ene rearrangement; [mc - H], with H from hydroxyl through a beta-ene or gamma-ene rearrangement, or from the alpha-carbon through an alpha-H-beta-ene rearrangement; or [mm] through charge-direct fragmentations. The beta-ene or gamma-ene facilitates the H shift to gamma position and alpha-cleavage. Deuterium labeling confirmed the assignment of MS/MS ions and the fragmentation mechanisms. Based on the MS/MS spectra and fragmentation mechanisms, we identified RvD1, PD1, and mono-hydroxy-DHA products in human neutrophils and blood, trout head-kidney, and stroke-injury murine brain-tissue.

Chromatography, High Pressure Liquid↗
PubMed2002

Kinetic characterization of the peptidase activity of Escherichia coli Lon reveals the mechanistic similarities in ATP-dependent hydrolysis of peptide and protein substrates.

Lon is an ATP-dependent protease that degrades unstructured proteins. In this study, we have examined the ATP dependency of Escherichia coli Lon catalyzing the hydrolysis of a defined fluorogenic peptide known as S3. Steady-state velocity analyses of S3 degradation in the presence of ATP, or the nonhydrolyzable ATP analogue AMPPNP, indicate a sequential mechanism, and the k(cat) of the reaction was 7-fold higher in the presence of ATP. Comparing the pre-steady-state time courses of the ATP- versus AMPPNP-mediated S3 hydrolysis reveals that ATP hydrolysis accelerates a slow step before the chemical cleavage of peptide. Product inhibition studies indicate that ADP is competitive versus ATP but noncompetitive versus the S3 substrate. In the absence of S3, Lon exhibits a 10-20-fold higher affinity for ADP than ATP. However the S3 substrate weakens the affinity of Lon for ADP by 7-19-fold, indicating that this peptide also promotes ADP/ATP exchange in Lon similar to that observed with protein substrates. The hydrolyzed peptide product, Pd1, exhibited noncompetitive inhibition versus both ATP and S3 substrates. Together with the small change in the K(i) of Pd1 at increasing S3 concentrations, the Pd1 inhibition data support the existence of an isomechanism in Lon catalyzing the hydrolysis of S3 in the presence of ATP or AMPPNP. Upon the basis of the collected data, an extended kinetic mechanism is proposed for the ATP-dependent peptidase mechanism of Lon.

ATP-Dependent Proteases↗
PubMed2005

The docosatriene protectin D1 is produced by TH2 skewing and promotes human T cell apoptosis via lipid raft clustering.

Docosahexaenoic acid, a major omega-3 fatty acid in human brain, synapses, retina, and other neural tissues, displays beneficial actions in neuronal development, cancer, and inflammatory diseases by mechanisms that remain to be elucidated. In this study we found, using lipid mediator informatics employing liquid chromatography-tandem mass spectrometry, that (10,17S)-docosatriene/neuroprotectin D1, now termed protectin D1 (PD1), is generated from docosahexaenoic acid by T helper type 2-skewed peripheral blood mononuclear cells in a lipoxygenase-dependent manner. PD1 blocked T cell migration in vivo, inhibited tumor necrosis factor alpha and interferon-gamma secretion, and promoted apoptosis mediated by raft clustering. These results demonstrated novel anti-inflammatory roles for PD1 in regulating events associated with inflammation and resolution.

Animals↗
PubMed1994

Downregulation of peptide transporter genes in cell lines transformed with the highly oncogenic adenovirus 12.

The expression of class I major histocompatibility complex antigens on the surface of cells transformed by adenovirus 12 (Ad12) is generally very low, and correlates with the high oncogenicity of this virus. In primary embryonal fibroblasts from transgenic mice that express both endogenous H-2 genes and a miniature swine class I gene (PD1), Ad12-mediated transformation results in suppression of cell surface expression of all class I antigens. Although class I mRNA levels of PD1 and H-2Db are similar to those in nonvirally transformed cells, recognition of newly synthesized class I molecules by a panel of monoclonal antibodies is impaired, presumably as a result of inefficient assembly and transport of the class I molecules. Class I expression can be partially induced by culturing cells at 26 degrees C, or by coculture of cells with class I binding peptides at 37 degrees C. Analysis of steady state mRNA levels of the TAP1 and TAP2 transporter genes for Ad12-transformed cell lines revealed that they both are significantly reduced, TAP2 by about 100-fold and TAP1 by 5-10-fold. Reconstitution of PD1 and H-2Db, but not H-2Kb, expression is achieved in an Ad12-transformed cell line by stable transfection with a TAP2, but not a TAP1, expression construct. From these data it may be concluded that suppressed expression of peptide transporter genes, especially TAP2, in Ad12-transformed cells inhibits cell surface expression of class I molecules. The failure to fully reconstitute H-2Db and H-2Kb expression indicates that additional factors are involved in controlling class I gene expression in Ad12-transformed cells. Nevertheless, these results suggest that suppression of peptide transporter genes might be an important mechanism whereby virus-transformed cells escape immune recognition in vivo.

ATP Binding Cassette Transporter, Subfamily B, Mem↗