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PubMed2005

Function of the family-9 and family-22 carbohydrate-binding modules in a modular beta-1,3-1,4-glucanase/xylanase derived from Clostridium stercorarium Xyn10B.

Clostridium stercorarium Xyn10B having hydrolytic activities on xylan and beta-1,3-1,4-glucan is a modular enzyme composed of two family-22 carbohydrate-binding modules (CBMs), a family-10 catalytic module of the glycoside hydrolases, a family-9 CBM, and two S-layer homologous modules, consecutively from the N-terminus. We investigated the function of family-9 and family-22 CBMs in a modular enzyme by comparing the enzymatic properties of a truncated enzyme composed of two family-22 CBMs and the catalytic module (rCBM22-CM), an enzyme composed of the catalytic module and family-9 CBM (rCM-CBM9), an enzyme composed of two family-22 CBMs, the catalytic module, and family-9 CBM (rCBM22-CM-CBM9), and the catalytic module polypeptide (rCM). Although the addition of family-9 CBM to rCM and rCBM22-CM did not significantly change catalytic activity toward xylan and beta-1,3-1,4-glucan, the addition of family-22 CBM to rCM and rCM-CBM9 drastically enhanced catalytic activity toward xylan and especially beta-1,3-1,4-glucan. Furthermore, the addition of family-22 CBM to rCM and rCM-CBM9 shifted the optimum temperature from 65 degrees C to 75 degrees C, but that of family-9 CBM to rCM and rCBM22-CM did not affect the optimum temperature. These facts suggest that the enzyme properties of Xyn10B were mainly dependent on the presence of the family-22 CBMs but not family-9 CBM.

Base Sequence↗
PubMed1995

Mechanisms subserving temporal modulation sensitivity in silent-cone substitution.

Temporal contrast sensitivity data were collected with sine-wave-modulated lights for achromatic, chromatic, and silent-cone-substitution stimuli. Achromatic (556- and 642-nm lights in phase) and chromatic (556- and 642-nm lights in counterphase) modulation sensitivities were measured at a constant time-average retinal illuminance of 1256 trolands (Td) and chromaticity of 595 nm. These data were considered to represent isolated temporal responses of luminance and red-green chromatic channels, respectively. Silent cone substitution was achieved with counterphase modulation of the 556- and the 642-nm lights and by suitable adjustment of the modulations or the radiances of the two lights. (1) The peak modulation depth of the 642-nm light was reduced to silence the long-wavelength-sensitive (LWS) cone, and the peak modulation depth of the 556-nm light was reduced to silence the middle-wavelength-sensitive (MWS) cone. These protocols maintained the time-average retinal illuminance and chromaticity as for the control conditions. (2) The luminance of the 642-nm light was decreased to silence the LWS cone and was increased to silence the MWS cone. In this procedure the time-average retinal illuminance and chromaticity differ for the silenced-LWS-cone (1047 Td and 589.5 nm) and the silenced-MWS-cone (4358 Td and 622 nm) conditions. The response modulation of the achromatic and the chromatic channels was calculated for the silent-substitution conditions. The chromatic channel is more sensitive at low frequencies, with a transition to greater achromatic channel sensitivity near 13 Hz for the silenced-LWS-cone condition and near 6 Hz for the silenced-MWS-cone condition.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2004

Coherence and polarization of electromagnetic beams modulated by random phase screens and their changes on propagation in free space.

The spectral degree of coherence and of polarization of some model electromagnetic beams modulated by a polarization-dependent phase-modulating device, such as a liquid-crystal spatial light modulator, acting as a random phase screen are examined on the basis of the recent theory formulated in terms of the 2 x 2 cross-spectral density matrix of the beam. The phase-modulating device is assumed to have strong polarization dependence that modulates only one of the orthogonal components of the electric vector, and the phase of the phase-modulating device is assumed to be a random function of position imitating a random phase screen and is assumed to obey Gaussian statistics with zero mean. The propagation of the modulated beam is also examined to show how the spectral degrees of coherence and of polarization of the beam change on propagation, even in free space. The results are illustrated by numerical examples.

Journal Article↗
PubMed2024

Design and evaluation of antisense sequence length for modified mouse U7 small nuclear RNA to induce efficient pre-messenger RNA splicing modulation in vitro.

Pre-messenger RNA (pre-mRNA) splicing modulation is an attractive approach for investigating the mechanisms of genetic disorders caused by mis-splicing. Previous reports have indicated that a modified U7 small nuclear RNA (U7 snRNA) is a prospective tool for modulating splicing both in vitro and in vivo. To date, very few studies have investigated the role of antisense sequence length in modified U7 snRNA. In this study, we designed a series of antisense sequences with various lengths and evaluated their efficiency in inducing splicing modulation. To express modified U7 snRNAs, we constructed a series of plasmid DNA sequences which codes cytomegalovirus (CMV) enhancer, human U1 promoter, and modified mouse U7 snRNAs with antisense sequences of different lengths. We evaluated in vitro splicing modulation efficiency using a luciferase reporter system for simple and precise evaluation as well as reverse transcription-polymerase chain reaction to monitor splicing patterns. Our in vitro assay findings suggest that antisense sequences of modified mouse U7 snRNAs have an optimal length for efficient splicing modulation, which depends on the target exon. In addition, antisense sequences that were either too long or too short decreased splicing modulation efficiency. To confirm reproducibility, we performed an in vitro assay using two target genes, mouse Fas and mouse Dmd. Together, our data suggests that the antisense sequence length should be optimized for modified mouse U7 snRNAs to induce efficient splicing modulation.

RNA, Small Nuclear↗
PubMed2004

The construction of movement with behavior-specific and behavior-independent modules.

Growing evidence suggests that different forms of complex motor acts are constructed through flexible combinations of a small number of modules in interneuronal networks. It remains to be established, however, whether a module simply controls groups of muscles and functions as a computational unit for use in multiple behaviors (behavior independent) or whether a module controls multiple salient features that define one behavior and is used primarily for that behavior (behavior specific). We used the Aplysia feeding motor network to examine the two proposals by studying the functions of identifiable interneurons. We identified three types of motor programs that resemble three types of behaviors that Aplysia produce: biting, swallowing, and rejection. Two ingestive programs (biting, swallowing) are defined by two movement parameters of the feeding apparatus (the radula): one is the same in both programs (phasing of radula closure motoneurons relative to radula protraction-retraction), whereas the other parameter (protraction duration) is different in the two programs. In each program, these two parameters were specified together by an individual neuron, but the neurons in each were different (B40 for biting, B30 for swallowing). These findings support the existence of behavior-specific modules. Furthermore, neuron B51 was found to mediate a phase that can be flexibly added on to both ingestive and egestive-rejection programs, suggesting that B51 may be a behavior-independent module. The functional interpretation of the role played by these modules is supported by the patterns of synaptic connectivity that they make. Thus, both behavior-specific and behavior-independent modules are used to construct complex behaviors.

Animals↗
PubMed2006

The circadian clock modulates core steps in long-term memory formation in Aplysia.

The circadian clock modulates the induction of long-term sensitization (LTS) in Aplysia such that long-term memory formation is significantly suppressed when animals are trained at night. We investigated whether the circadian clock modulated core molecular processes necessary for memory formation in vivo by analyzing circadian regulation of basal and LTS-induced levels of phosphorylated mitogen-activated protein kinase (P-MAPK) and Aplysia CCAAT/enhancer binding protein (ApC/EBP). No basal circadian regulation occurred for P-MAPK or total MAPK in pleural ganglia. In contrast, the circadian clock regulated basal levels of ApC/EBP protein with peak levels at night, antiphase to the rhythm in LTS. Importantly, LTS training during the (subjective) day produced greater increases in P-MAPK and ApC/EBP than training at night. Thus, circadian modulation of LTS occurs, at least in part, by suppressing changes in key proteins at night. Rescue of long-term memory formation at night required both facilitation of MAPK and transcription in conjunction with LTS training, confirming that the circadian clock at night actively suppresses MAPK activation and transcription involved in memory formation. The circadian clock appears to modulate LTS at multiple levels. 5-HT levels are increased more when animals receive LTS training during the (subjective) day compared with the night, suggesting circadian modulation of 5-HT release. Circadian modulation also occurred downstream of 5-HT release because animals treated with 5-HT to induce LTS exhibited significantly greater LTS when treated during the (subjective) day compared with the night. Together, our studies suggest that the circadian clock modulates LTS at multiple steps and locations during the formation of long-term memory.

Animals↗
PubMed2004

Potential for transport of boll weevils (Coleoptera: Curculionidae) to the cotton gin within cotton modules.

There is concern that cotton gins located in boll weevil, Anthonomus grandis grandis Boheman, eradication zones serving customers in adjacent infested zones may serve as a site for boll weevil reintroductions if weevils are transported alive inside cotton modules. We surveyed fields in three distinct areas of Texas and found that weevils can be present in large numbers in cotton fields that have been defoliated and desiccated in preparation for harvest, both as free adults and as immatures inside unopened bolls. Harvested cotton taken from module builders indicated that approximately = 100-3700 adult boll weevils were packed inside modules constructed at the sampled fields. Marked weevils were forced through a laboratory field cleaner (bur extractor) commonly mounted on stripper-harvesters, and 14% were recovered alive in the seed cotton fraction and lived at least to 24 h. Survival of weevils placed inside modules declined over time up to 7 d, but the magnitude of the decline varied with experimental conditions. In one experiment, 91% of the weevils survived to 7 d, whereas under harsher environmental conditions, only 11% survived that long. Together, our results indicate that when cotton is harvested in an infested area, boll weevils likely will be packed alive into cotton modules, and many will still be alive by the time the module is fed into the gin, at least up to 7 d after the module's construction.

Agriculture↗
PubMed2004

Acute neurosteroid modulation and subunit isolation of the gamma-aminobutyric acidA receptor in the bullfrog, Rana catesbeiana.

The inhibitory neurotransmitter gamma-aminobutyric acid (GABA) has multiple receptors. In mammals, the GABA(A) receptor subtype is modulated by neurosteroids. However, whether steroid interaction with the GABA(A) receptor is unique to mammals or a conserved feature in vertebrates is unknown. Thus, neurosteroid modulation of the GABA(A) receptor was investigated in the brain of the bullfrog (Rana catesbeiana) using the mammalian GABA(A) receptor agonist [(3)H]muscimol. Two neurosteroids, allopregnanolone and pregnenolone sulfate, affected [(3)H]muscimol specific binding in bullfrog brain membrane preparations. Allopregnanolone significantly increased [(3)H]muscimol specific binding in a dose- and time-dependent manner. The pattern of allopregnanolone modulation supports the hypothesis that the bullfrog brain possesses both high-affinity and low-affinity [(3)H]muscimol binding sites. Unlike allopregnanolone, pregnenolone sulfate showed biphasic modulation with increased [(3)H]muscimol specific binding at low nanomolar concentrations and decreased specific binding at micromolar concentrations. Additionally, three cDNA fragments with significant homology to mammalian GABA(A) receptor subunits were isolated from the bullfrog brain. These fragments belong to the alpha1, beta1, and gamma2 subunit families. In mammals, GABA(A) receptors composed of these specific subunit isoforms are effectively modulated by neurosteroids, including allopregnanolone. Neurosteroid modulation of the amphibian brain GABA(A) receptor is therefore supported by both [(3)H]muscimol binding studies and subunit sequences. Allopregnanolone and pregnenolone sulfate modulation of this receptor may thus represent a significant mechanism for steroid influence on amphibian brain and behavior.

Amino Acid Sequence↗
PubMed2003

Periodontal host modulation with antiproteinase, anti-inflammatory, and bone-sparing agents. A systematic review.

BACKGROUND: The use of modulating agents, including inhibition of matrix metalloproteinases (MMPs) with antiproteinases, blocking production of proinflammatory cytokines and prostaglandins with anti-inflammatory drugs, and inhibiting activation of osteoclasts with bone-sparing agents, has been postulated to be of therapeutic value as an adjunctive therapy to the management of chronic periodontitis. RATIONALE: The objective of this systematic review of the literature was to assess the adjunctive efficacy of antiproteinase, anti-inflammatory, and bone-sparing host-modulating agents in the treatment of gingivitis, aggressive periodontitis, and chronic periodontitis. FOCUSED QUESTIONS: 1. In patients with periodontal diseases, what is the effect of host-modulation agents, alone or combined with conventional therapy, compared to conventional therapy alone as assessed by clinical, radiographic, adverse, and patient-centered outcomes? 2. In patients with dental implants, what is the effect of host-modulation agents on implant success assessed by clinical, radiographic, adverse, and patient-centered outcomes? SEARCH PROTOCOL: MEDLINE, Embase, and the Cochrane Library databases were searched without language restrictions through April 1, 2002 for studies that used tetracycline (TET)-related matrix metalloproteinase (MMP) inhibitors, or non-steroidal anti-inflammatory drugs (NSAIDs) and bisphosphonate anti-osteolytic agents. The investigation also included hand searching of journals and contacting authors and industry experts. SELECTION CRITERIA INCLUSION CRITERIA: Only human studies (randomized controlled clinical trials, cohort studies, case-control studies, cross-sectional studies, and case series) were selected. Studies were on subjects with gingivitis, aggressive or chronic periodontitis, or dental implants. Interventions included TET-related MMP inhibitors, NSAIDs, or bisphosphonate anti-osteolytic agents. EXCLUSION CRITERIA: Studies that used MMP tissue inhibitors as diagnostic or prognostic indicators of periodontal disease or that evaluated short-term systemic antibodies or locally delivered levels of drugs with antiproteinase activity were excluded. DATA COLLECTION AND ANALYSIS: The primary outcomes for assessment were changes in bone or clinical attachment levels (CAL); secondary outcomes included clinical measures of plaque, gingival inflammation, probing depth (PD), and mobility. Summary data appropriate for meta-analysis were pooled using a weighted average and analyzed using a standardized difference; the results were checked with both fixed-effects and random-effects models. MAIN RESULTS: 1. A meta-analysis done on the studies reporting changes in CAL and PD following administration of sub-antimicrobial doses of doxycycline (SDD) in conjunction with scaling and root planing (SRP) in patients with periodontitis showed a statistically significant beneficial adjunctive effect. 2. There were insufficient data to provide meta-analyses on periodontal patients treated with other host-modulating agents; descriptive tables are included. 3. NSAIDS show promise in their ability to slow periodontal disease. 4. Preliminary data on bisphosphonate agents indicate there is a potential role for these agents in periodontitis management. 5. There are a very limited number of studies on host-modulating agents and dental implants and no analyses were possible. 6. Because the treatment methodologies and clinical variables differed considerably among the studies, it is difficult to summarize the information and identify a reliable total patient population. REVIEWERS' CONCLUSIONS: 1. Large multi-center trials are needed to evaluate the role of host-modulating agents in the treatment of periodontitis. 2. NSAIDS and bisphosphonate drugs may have a potential adjunctive role in periodontal therapy. 3. The adjunctive use of SDD with SRP is statistically more effective than SRP alone in reducing PD and in achieving CAL gain.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1984

Modulation of receptor sensitivity and action potentials by transmitters in vertebrate neurones.

The nicotinic cholinergic transmission causing generation of the fast EPSP in bullfrog sympathetic ganglia is modulated by the action of transmitters or hormones other than ACh. In general, a synaptic transmission appears to be modulated in a variety of ways by the action of many kinds of transmitters or hormones in the vertebrate neural system. There are at least four different types of modulatory actions of these endogenous substances on a synaptic transmission; namely, 1) modulation of the amount of the transmitter released from presynaptic neurones, 2) modulation of the sensitivity of the receptors of postsynaptic neurones, 3) modulation of the resting membrane potential or conductance of postsynaptic neurones, 3) modulation of the resting membrane potential or conductance of postsynaptic neurones, and 4) modulation of the configuration of the action potential of postsynaptic neurones. In the present review, the experimental evidence supporting the modulatory actions of endogenous substances on the receptor sensitivity and the action potential of postsynaptic neurones was reviewed. The mechanisms underlying these two types of modulatory actions were also briefly discussed.

Acetylcholine↗
PubMed2006

Phenothiazines and structurally related compounds as modulators of cancer multidrug resistance.

Phenothiazines and structurally related compounds alongside their other biological activities are able to modulate multidrug resistance (MDR) in tumor cells. The extensive investigations on their MDR modulation effects consist part of the efforts to overcome MDR - the major obstacle in cancer chemotherapy. In this article we try to systematize the results collected in the last two decades in two main aspects. The first one comprises the mechanism of modulation by phenothiazine-type MDR modulators. Two main possible mechanisms of MDR reversal are reviewed: (i) direct interaction with Pgp; (ii) interactions with membrane phospholipids. The second aspect relates to the structural properties of phenothiazines and related compounds responsible for their MDR reversing effect. The structural alerts and physicochemical properties influencing anti-MDR activity are considered as identified by structure--activity (SAR) or quantitative structure--activity relationship (QSAR) studies. Results discussed in the article point to MDR modulation by phenothiazines and related compounds as a complex process in which more than one mechanism are certainly involved. Further investigations in this direction should contribute to elucidation of the possible mechanisms of MDR modulation by these compounds. On the basis of the studies discussed the potential use of phenothiazine-type MDR modulators as a model system in the further investigations of the MDR phenomenon is outlined.

Animals↗
PubMed2000

Modulations of primary visual cortex activity representing attentive and conscious scene perception.

In the visual cortex, information is transferred from one area to the next by means of feedforward connections. These connections shape the receptive field properties of neurons in subsequent visual areas. Horizontal and feedback connections modulate this neuronal activity, resulting in the phenomenon of contextual modulation. In area V1, where receptive field properties reflect only low level processing, contextual modulation can be observed that represents fully evaluated perceptual saliency of the features within the receptive field. Here, we discuss to what extent these modulations are related to high level visual processes like perceptual organization, attention and visual awareness. Contextual modulation appears to reflects a process very distinct from receptive field based processing. This process seems to integrate information from distant areas in visual cortex to neurophysiologically 'highlight' those neurons that represent image elements or features of objects that stand out perceptually. Moreover, similar modulations are observed in relation to whether objects are attended to or not. Finally, these modulations are only present when subjects are aware of the visual input.

Animals↗
PubMedDate not supplied

Modulation of mean eye position during vestibular induced eye movements of the rhesus monkey.

Vestibular induced nystagmus in the dark was measured during sinusoidal rotational stimulation in three male monkeys using electrooculography. A periodic modulation of mean eye position was observed. This periodic modulation was quantified by least squares fitting through the nystagmus a sinusoid whose frequency was the same as that of the stimulus. The magnitude and the phase of the best fitting sinusoid were used to determine gain and phase delay at various combinations of stimulus amplitudes and frequency. Results indicate that the mean eye position in the alert animals is predominantly modulated in the direction of the fast component of nystagmus. The magnitude of this modulation of mean eye position is independent of the amplitude of the stimulus. The phase relationship of this modulation is dependent on the frequency of stimulation. In drowsy animals, the modulation of mean eye position is predominantly in the direction of the slow component of nystagmus. We conclude that the modulation of mean eye position during vestibular induced nystagmus operates as an automatic gain control system which is sensitive to the animal's level of alertness. The quantitative data in this report are useful in refining current models of vestibular nystagmus.

Animals↗
PubMed2000

Measurement of the temporal-modulation transfer function for a single listener with cochlear hearing loss and left-hemisphere damage.

The modulation depth required for the detection of sinusoidal amplitude-modulation applied to a white noise carrier was measured as a function of modulation frequency, giving temporal modulation transfer functions (TMTFs). Five adult listeners with normal hearing (mean age 52 years), five elderly listeners with moderate cochlear hearing loss (mean age 66 years) and a single elderly listener (aged 73 years) with moderate cochlear hearing loss and left-hemisphere damage were tested in the right ear at 50 dB SL. The five elderly listeners were matched in audiogram with the brain-damaged listener. Modulation detection was systematically poorer than normal in the five elderly listeners with cochlear hearing loss. However, their TMTFs were lowpass in shape, as for the five normal-hearing adult listeners. Modulation detection was much poorer in the elderly listener with cochlear hearing loss and left-hemisphere damage compared to the five normal-hearing adults and the five elderly listeners with cochlear hearing loss. Moreover, modulation detection was poorer at 4, 64 and 128 Hz than at 8, 16 and 32 Hz in the brain-damaged listener, giving his TMTF a bandpass appearance. These results are in agreement with the hypothesis that the main factors limiting the ability to detect changes in the temporal-envelope of sounds are located at a central (retro-cochlear) level of the auditory system rather than at a peripheral (cochlear) level. They also suggest that the TMTF approach may prove useful in distinguishing peripheral and central hearing losses.

Aged↗
PubMed1987

Glycosaminoglycans and a newly purified aortic chondroitin proteoglycan block polycationic modulation of protein phosphatase activity.

Recently, we described a bovine aortic phosphatase which we called PCM-phosphatase (polycation modulable) because its activity in vitro can be modulated by polycations such as polylysine and histone-H1 (Di Salvo J, Gifford D, Kokkinakis A. Modulation of aortic protein phosphatase activity by polylysine. Proc Soc Exp Biol Med 177:24-32, 1984). We We suspected that polycationic modulation might be inhibited by polyanionic glycosaminoglycans. Accordingly, an aortic anionic substance was purified by sequential steps including (a) heating aortic extracts at 90 degrees C, (b) precipitation of protein with (NH4)2 SO4, and (c) anionic-exchange chromatography on a Mono Q HR 5/5 column using the Pharmacia fast protein liquid chromatography system. Electrophoresis (polyacrylamide-agarose) of the purified substance revealed one band which stained metachromatically with toluidine blue; however, no staining occurred with Coomassie blue. Electrophoretic mobility increased following proteolytic digestion of the substance with papain. The substance produced concentration-dependent reversal of polylysine-mediated inhibition of myosin light chain dephosphorylation, and it also reversed polylysine-mediated stimulation of phosphorylase phosphatase activity expressed by PCM-phosphatase. Its ability to inhibit or reverse polycationic modulation was abolished after incubation with either chondroitinase AC or chondroitinase ABC. Based on these properties the substance was identified as a chondroitin proteoglycan. Commercially available glycosaminoglycans (heparin and chondroitin sulfates) also reversed polycationic modulation. The results show that modulation of phosphatase activity may be significantly modified by naturally occurring glycosaminoglycans. These studies may also have an important bearing on the purported roles of phosphatase(s) and glycosaminoglycans in calcification of soft tissues.

Animals↗
PubMed2003

Cell cycle modulators for the treatment of lung malignancies.

It has become clear in the past decade that most human malignancies, including lung neoplasms, have aberrations in cell cycle control. The tumor suppressor gene retinoblastoma is an important player in the G1/S transition and its function is abnormal in most human neoplasms. Retinoblastoma function is lost as a result of phosphorylation by the cyclin-dependent kinases (CDKs). Thus, modulation of CDKs may have an important use for the therapy and prevention of human neoplasms. Direct CDK modulators are small molecules that target specifically the adenosine triphosphate binding site of CDKs. In contrast, indirect CDK modulators affect CDK function by modulation of upstream pathways required for CDK activation. The first example of a direct small-molecule CDK modulator tested in the clinic, flavopiridol, is a pan-CDK inhibitor that not only promotes cell cycle arrest but also halts transcriptional elongation, promotes apoptosis, induces differentiation, and has antiangiogenic properties. The second example of direct small-molecule CDK modulators tested in clinical trials is UCN-01 (7-hydroxystaurosporine). UCN-01 has interesting preclinical features: it inhibits Ca2+-dependent protein kinase C, promotes apoptosis, arrests cell cycle progression at G1/S, and abrogates checkpoints upon DNA damage. In summary, novel small-molecule CDK modulators are being tested in the clinic with interesting results. Although these small molecules are directed toward a very prevalent cause of carcinogenesis, their role in the clinical armamentarium is still uncertain.

Antineoplastic Agents↗
PubMed1998

The effect of spherical and other aberrations upon the modulation transfer of the defocussed human eye.

Relative modulation transfer is defined as contrast sensitivity under blur normalised to contrast sensitivity at optimum focus. Measured relative modulation transfer exceeds relative modulation transfer as calculated for aberration free optics at higher spatial frequencies (> 2 cpd). The contribution of spherical aberration to this discrepancy was studied. In the case of positive blur, spherical aberration increases relative modulation transfer for spatial frequencies of approximately 4 cpd and over. However, spherical aberration does not explain the entire difference between measured and calculated relative modulation transfer. Chromatic aberration does not provide a noticeable additional explanation. With negative blur, spherical aberration increases the relative modulation transfer much more. The effect of other monochromatic aberrations on relative modulation transfer is discussed.

Contrast Sensitivity↗
PubMed1999

Identification of an oxygen-responsive element in the 5'-flanking sequence of the rat cytosolic phosphoenolpyruvate carboxykinase-1 gene, modulating its glucagon-dependent activation.

The glucagon-stimulated transcription of the cytosolic phosphoenolpyruvate carboxykinase-1 (PCK1) gene is mediated by cAMP and positively modulated by oxygen in primary hepatocytes. Rat hepatocytes were transfected with constructs containing the first 2500, 493 or 281 bp of the PCK1 5'-flanking region in front of the chloramphenicol acetyltransferase (CAT) reporter gene. With all three constructs glucagon induced CAT activity with decreasing efficiency maximally under arterial pO2 and to about 65% under venous pO2. Rat hepatocytes were then transfected with constructs containing the first 493 bp of the PCK1 5'-flanking region in front of the luciferase (LUC) reporter gene, which were block-mutated at the CRE1 (cAMP-response element-1; -93/-86), putative CRE2 (-146/-139), promoter element (P) 1 (-118/-104), P2 (-193/-181) or P4 (-291/-273) sites. Glucagon induced LUC activity strongly when the P1 and P2 sites were mutated and weakly when the P4 site was mutated; induction of the P1, P2 and P4 mutants was positively modulated by the pO2. Glucagon also induced LUC activity strongly when the putative CRE2 site was altered; however, induction of the CRE2 mutant was not modulated by the pO2. Glucagon did not induce LUC activity when the CRE1 site was modified. These experiments suggested that the CRE1 but not the putative CRE2 was an essential site necessary for the cAMP-mediated PCK1 gene activation by glucagon and that the putative CRE2 site was involved in the oxygen-dependent modulation of PCK1 gene activation. To confirm these conclusions rat hepatocytes were transfected with simian virus 40 (SV40)-promoter-driven LUC-gene constructs containing three CRE1 sequences (-95/-84), three CRE2 sequences (-148/-137) or three CRE1 sequences plus two CRE2 sequences of the PCK1 gene in front of the SV40 promoter. Glucagon induced LUC activity markedly when the CRE1, but not when the CRE2, sites were in front of the SV40-LUC gene; however, induction of the (CRE1)3SV40-LUC constructs was not modulated by the pO2. Glucagon also induced LUC activity very strongly when the CRE1 and CRE2 sites were combined; induction of the (CRE1)3(CRE2)2SV40-LUC constructs was positively modulated by the pO2. These findings corroborated that sequences of the putative CRE2 site were responsible for the modulation by oxygen of the CRE1-dependent induction by glucagon of PCK1 gene transcription.

Animals↗