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PubMed1988

Human cDNAs rap1 and rap2 homologous to the Drosophila gene Dras3 encode proteins closely related to ras in the 'effector' region.

We have characterized two new ras-related genes rap1 and rap2 from a human cDNA library, by hybridization with the Drosophila Dras3 gene at low stringency conditions. The rap1 and rap2 genes encode proteins of 184 and 183 amino acid respectively with molecular weights of 20.9 kd and 20.7 kd. These proteins are 53% and 46% identical to the human K-ras protein and share several properties with the classical ras proteins. The C-terminal cysteine involved in the membrane anchoring as well as the GTP binding regions of the p21 ras proteins are present in the rap proteins suggesting that these proteins could bind GTP/GDP and have a membrane localization. The most striking difference between the rap and ras proteins resides in their 61st amino acid. As in the Drosophila Dras3 protein, both rap proteins have a threonine instead of the glutamine found at position 61 of the classical ras proteins. Furthermore the putative effector domain of the ras proteins is strictly conserved in the rap1 protein whereas only one amino acid difference is found in the rap2 protein. This suggests that the rap proteins might interact with the same effector as the ras proteins.

Amino Acid Sequence↗

PubMed2002

Identification of differentially expressed genes in rheumatoid arthritis by a combination of complementary DNA array and RNA arbitrarily primed-polymerase chain reaction.

OBJECTIVE: There is increasing evidence that T cell-independent pathways, such as the up-regulation of protooncogenes and the production of growth factors and matrix-degrading enzymes, lead to progressive destruction of affected joints. Therefore, identification of differentially regulated genes restricted to rheumatoid arthritis (RA) synovial fibroblasts is essential. A combination of RNA arbitrarily primed-polymerase chain reaction (RAP-PCR) and complementary DNA (cDNA) array with defined genes was used for a highly sensitive differential screening using small amounts of RNA. METHODS: RNA was extracted from cultured synovial fibroblasts obtained from 6 patients with RA and 6 patients with osteoarthritis (OA). RAP-PCR was performed using different arbitrary primers for first- and second-strand synthesis. PCRs were hybridized to cDNA array membranes. RA samples were compared with OA samples for differentially expressed genes. RESULTS: In contrast to standard cDNA array, the identification of 12 differentially expressed genes in RA compared with OA (approximately 6%) was possible. Differentially expressed genes of interest were confirmed using semiquantitative RT-PCR and in situ hybridization. CONCLUSION: Numerous variants of the differential display method and continuous improvements, including RAP-PCR, have proven to be both efficient and reliable for examining differentially regulated genes. Our results show that RAP-PCR combined with cDNA arrays is a suitable method for identifying differentially expressed genes in rheumatoid synovial fibroblasts, using very small amounts of RNA.

Arthritis, Rheumatoid↗

PubMed1990

Pouch size: the important functional determinant after restorative proctocolectomy.

Sixty-seven patients with a J-shaped ileonanal pouch were studied over a 2-year period with regular recording of sphincter and pouch characteristics and analysis of their role in functional outcome. Although there was a 27 per cent permanent reduction in resting anal pressure (RAP) (P less than 0.001), two-thirds of the patients still had a RAP within the normal range. The mean(s.d.) pouch volume increased during the first year from 132(46) ml to 282(85) ml. RAP was not related to functional outcome and preoperative RAP was not predictive of subsequent function. Large pouch volume and compliance correlated with low defaecation frequency (range of r = 0.27-0.36; P less than 0.05) and good overall function (r = 0.37-0.56; P less than 0.01). The initial pouch volume was predictive of subsequent overall function. The ileal length used for pouch construction predicted subsequent pouch volume (r = 0.48; P less than 0.001) and to some extent functional outcome (r = 0.28-0.37; P less than 0.05). However, the studied variables accounted for only 21 per cent of the total variance of functional outcome.

Adolescent↗

PubMed1979

Tricuspid regurgitation: clinical and angiographic assessment.

Because previous attempts to diagnose and quantitate tricuspid regurgitation (TR) by angiography have been unreliable, 60 patients with mitral or combined mitral and aortic valve disease had right ventriculography using a special preshaped catheter. A clinical diagnosis of TR was confirmed in 45% of the patients with moderate and severe TR. A pansystolic murmur increasing in intensity with inspiration, a pulsatile liver, and a prominent CV wave in the jugular veins when present together were specific for severe TR but were seen in only 30% of the patients with severe TR but were seen in only 30% of the patients with severe TR (3+ or 4+). Ventricularization of the right atrial pressure contour was specific for severe TR but was seen in only 40% of the patients with severe TR. A normal right atrial mean pressure (RAP) did not exclude TR, but a rise in RAP or an unchanged RAP with deep inspiration was seen in all patients with TR. Similar findings were observed in two patients with severe pulmonary hypertension who had no TR. There was no relation between the magnitude of this rise in RAP, the degree of pulmonary hypertension, and the severity of TR. The use of a special preshaped catheter tends to avoid the induction of premature beats, and right ventriculograms with a preshaped catheter may be useful in diagnosing TR.

Blood Pressure↗

PubMed2000

Relationship between mean right atrial pressure and Doppler parameters in patients with right ventricular infarction.

BACKGROUND: The incidence of an inferior left ventricular infarction involving the right ventricle is very high, ranging from 14 to 84%. Isolated right ventricular infarction accounts for < 3% of all cases of infarction. HYPOTHESIS: The aim of the present study was to assess the relationship between Doppler parameters of hepatic vein and tricuspid inflow, as well as mean right atrial (RA) pressure in patients with right ventricular infarction. METHODS: In all, 59 consecutive patients with inferior left ventricular infarction involving the right ventricle were selected for the study. All patients underwent Doppler echocardiographic evaluation of tricuspid and hepatic vein parameters and catheterization of the right side of the heart. Patients were divided into two groups according to the presence or absence of severe tricuspid regurgitation. RESULTS: In patients with severe tricuspid regurgitation, a significant correlation (r = 0.64; p < 0.001) between RA maximal volume and mean right atrial pressure (RAP) was found, and the sensitivity of RA maximal volume in identifying mean RAP > 7 mmHg was 64% with a specificity of 78%. In patients without severe tricuspid regurgitation, the most significant relationship was observed between mean RAP and inferior vena cava collapse index. Significant correlations between maximal and minimal diameters of the inferior vena cava were also observed. CONCLUSIONS: Echocardiographic and Doppler parameters may be useful for evaluating mean RAP in patients with right ventricular infarction. In patients with severe tricuspid regurgitation, the more important parameters are maximal and minimal RA volumes. In patients without severe tricuspid regurgitation together with right atrial volume, the important parameters are acceleration and deceleration time of the tricuspid inflow peak E velocity and hepatic systolic and diastolic venous flow.

Aged↗

PubMed2004

Use of RNA-arbitrarily-primed PCR to detect the induction of gene expression in freshwater bivalves (Unio tumidus) transplanted into the Moselle River.

RNA-arbitrarily-primed PCR (RAP-PCR) can be used to detect changes in gene expression in organisms for which only minimal genomic information is available. In this study, RAP-PCR was used to detect modification of mRNA expression in the freshwater bivalve Unio tumidus, a mussel commonly used as a sentinel species in field studies. RNA expression was analyzed in the digestive glands of mussels from a control pond and in mussels transplanted into two sites on the Moselle River. The analysis identified a product in all animals exposed to sediments at the river station located downstream of a heavily populated area. This product was not present in animals exposed at the upstream station or at the control site. The additional PCR product was cloned and sequenced, and specific oligonucleotides for the sequence were designed to amplify cDNAs from control and transplanted mussels. A signal was obtained only with the cDNAs from animals exposed at the downstream station, confirming that the variation detected by RAP-PCR corresponds to an increase of gene expression. Chemical analysis of sediments from the control and river sites indicated that the levels of several potential pollutants were similar at the three locations and below currently accepted pollution thresholds. Our results indicate that RAP-PCR is a sensitive technique that can be applied in field studies to identify modifications in the gene expression of bioindicator species. This approach can complement chemical, biochemical and population studies to assess the impact of human activity on the ecological quality of aquatic systems.

Amino Acid Sequence↗

PubMed2002

Low-density lipoprotein receptor-related protein mediates in PC12 cell cultures the inhibition of nerve growth factor-promoted neurite outgrowth by pregnancy zone protein and alpha2-macroglobulin.

Human pregnancy zone protein (PZP) is a major pregnancy-associated plasma protein closely related to human alpha(2)-macroglobulin (alpha(2)M). It has been demonstrated that monoamine-activated forms of human and rat alpha(2)M and rat alpha(1)M can bind to TrkA and, respectively, inhibit and stimulate NGF-promoted neurite outgrowth, Trk phosphorylation, and intracellular signal transduction in PC12 cells. However, the effect of PZP on neurons is unknown, and the molecular mechanism of neuroinhibition by monoamine-activated alpha(2)M is still unclear. In this report, we show that methylamine-activated PZP (MA-PZP), like MA-alpha(2)M, inhibits in a dose-dependent way the NGF-promoted neurite extension and TrkA phosphorylation in PC12 cells. On the other hand, normal PZP (N-PZP) had little or no effect. In addition, the inhibitory effect of activated alpha-macroglobulins (alphaMs) was reversible upon its removal from the cell culture. In addition, PZP, as well as alpha(2)M, is neuroinhibitory without being directly cytotoxic. It is known that the activated alphaMs bind to the multiligand receptor termed low-density lipoprotein receptor-related protein (LRP) and that the receptor-associated protein (RAP) specifically blocks uptake of all known LRP ligands. To investigate the potential role of LRP in neuromodulation by activated PZP/alpha(2)M, the effect of RAP on the neuroinhibitory activities of these alphaMs was also studied. Data presented here show that RAP blocked the neurite- and Trk-inhibitory activities of both MA-PZP and MA-alpha(2)M, whereas RAP itself had no neuromodulatory effect. Hence, we conclude that these data suggest that the LRP receptor and its alphaM ligands may play a role in regulating Trk receptors.

Analysis of Variance↗

PubMed2006

Proteomic analysis of anti-angiogenic effects by a combined treatment with vinblastine and rapamycin in an endothelial cell line.

Angiogenesis controls the new blood supply routes into the tumor mass via the host endothelial cells (ECs). In this study, the EA.hy926 endothelial cell line has been treated with vinblastine (VBL) and rapamycin (RAP), both separately and in combination at low doses. Recently, we demonstrated the synergistic antiangiogenic effects of a combination of VBL and RAP at very low doses in vitro and in vivo. Herein, we confirm the ability of this combined treatment to statistically inhibit the proliferation of ECs, in a synergistic manner, by inducing apoptosis. The aim of this study was to substantiate these findings at the protein level. Differential proteomic analysis was performed on untreated control cells, treated with VBL, incubated with RAP, or subjected to a drug combination. Differentially expressed 113 polypeptide chains were visualized and 65 were identified via MALDI-TOF analysis. Some of the regulated proteins are involved in the processes of angiogenesis, proliferation, migration, and apoptosis. The down-modulation of ATP synthase, annexin A2, heat shock p70, glucose-6-phosphate dehydrogenase, vasodilator-stimulated phosphoprotein, proteasome 26S, tryptophanyl-tRNA synthetase, and stathmin/OP18, as well as the up-modulation of carbonyl reductase, Rho-GDI, and histone H1.0 correlates with the synergistic antiangiogenic activity of VBL and RAP.

Angiogenesis Inhibitors↗

PubMed1996

Characterization of alpha 2-macroglobulin binding to human trabecular meshwork cells: presence of the alpha 2-macroglobulin signaling receptor.

Direct binding of receptor-recognized alpha 2-macroglobulin (alpha 2M*) or a cloned receptor binding fragment from rat alpha 1-macroglobulin (RBF) to human trabecular meshwork cells demonstrated two classes of cell surface binding sites. One class has an apparent Kd of 5.0 nM and a receptor number of 31,800 receptors/cell. The other class has an apparent Kd of 20 pM and a receptor number of 1600 receptors/cell. Binding studies of alpha 2M* or RBF in the presence of a competitor for binding to low-density-lipoprotein receptor-related protein/alpha 2M* receptor (LRP/alpha 2MR) called receptor-associated protein (RAP) show that only the lower affinity class of binding sites is susceptible to competition with RAP. Uptake studies demonstrate specific internalization and degradation of alpha 2M* which is inhibitable by RAP. Exposure of the cells to alpha 2M* and RBF (40 nM) is associated with mean increases of 171 and 210%, respectively, in the intracellular calcium concentration, which is not inhibitable by RAP or pertussis toxin. These studies present the first characterization of alpha 2M* and RBF signaling in a primary human cell type and suggest a role for alpha 2M* in the physiology of the eye.

Aged↗

PubMed1996

A novel collection of accessory factors associated with yeast RNA polymerase II.

A relatively simple subset of general transcription factors is sufficient for transcript initiation by RNA polymerase II. However, a recently identified "holoenzyme" contains additional accessory proteins required for mediating signals from some activators (Y-J. Kim et al., 1994, Cell 77, 599-608; A. Koleske and R. Young, 1994, Nature 368, 466-469). By immobilizing RNA polymerase II and associated proteins (RAPs) from a transcriptionally active yeast extract, we have identified a novel collection of proteins distinct from those found in the holoenzyme. The eluted RAP fraction did not contain the holoenzyme components Srb2,4,5 + 6p, Gal11p, or Sug1p, but did include the known transcription factors TFIIB and TFIIS and the three subunits of yeast TFIIF (Ssu71p/Tfg1p, Tfg2p, and Anc1p/Tfg3p). Also isolated as RAPs are two proteins (Cdc73p and Paf1p) with interesting connections to gene expression. Mutations in CDC73 and PAF1 affect cell growth and the abundance of transcripts from a subset of yeast genes (X. Shi et al., Mol. Cell. Biol., 1996 16, 669-676). The RAP fraction may therefore define one or more functional forms of RNA polymerase II distinct from the activator-mediating holoenzyme.

Amino Acid Sequence↗

PubMed1994

Right atrial pressure and forearm blood flow during prolonged exercise in a hot environment.

Right atrial pressure (RAP) at rest is known to be reduced by an increase in skin blood flow (SkBF) in a hot environment. However, there is no clear evidence that this is so during exercise. To clarify the effect of the increase in SkBF on RAP during exercise, we measured forearm blood flow (FBF) (as an index of SkBF) and RAP continuously using a Swan-Ganz catheter in five male volunteers exercising on a cycle ergometer at 60% of peak aerobic power for 50 min in a hot environment (30 degrees C, relative humidity 20%). Cardiac output increased from 5.5 +/- 0.2 l/min at rest to 17.9 +/- 1.2 l/min (mean +/- SE, P < 0.01) in the first 10 min of exercise and then remained steady until the end of exercise. FBF did not change significantly during the first 5 min, but then increased from 2.7 +/- 0.5 ml/100 ml per min at rest to 10.8 +/- 1.7 ml/100 ml per min (P < 0.001) by 25 min as pulmonary arterial blood temperature (Tb) rose from 37.0 +/- 0.1 degrees C to 38.1 +/- 0.1 degrees C (P < 0.001). FBF then reached a plateau, despite a continuing increase in Tb. RAP increased significantly from 4.3 +/- 0.8 to 7.6 +/- 1.2 mm Hg (P < 0.001) during the first 5 min of exercise and then gradually declined to 6.1 +/- 1.0 mm Hg by 25 min (P < 0.001 vs. 5 min) and further to 5.7 +/- 1.0 mm Hg by 50 min, a value not significantly higher than at rest.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1987

Autoregulation of renal blood flow, glomerular filtration rate and renin release in conscious dogs.

The relationship between renal artery pressure (RAP), renal blood flow (RBF), glomerular filtration rate (GFR) and the renal venous-arterial plasma renin activity difference (PRAD) was studied in 22 chronically instrumented, conscious foxhounds with a daily sodium intake of 6.6 mmol/kg. RAP was reduced in steps and maintained constant for 5 min using an inflatable renal artery cuff and a pressure control system. Between 160 and 81 mm Hg we observed a concomitant autoregulation of GFR and RBF with a high precision. The "break off points" for GRF- and RBF-autoregulation were sharp and were significantly different from each other (GFR: 80.5 +/- 3.5 mm Hg; RBF: 65.6 +/- 1.3 mm Hg; P less than 0.01). In the subautoregulatory range GFR and RBF decreased in a linerar fashion and ceased at 40 and 19 mm Hg, respectively. Between 160 mm Hg and 95 mm Hg (threshold pressure for renin release) PRAD remained unchanged; below threshold pressure PRAD increased steeply (average slope: 0.34 ng AI.ml-1.h-1.mm Hg-1) indicating that resting renin release may be doubled by a fall of RAP by only 3 mm Hg. At the "break-off point" of RBF-autoregulation (66 mm Hg) renin release was 10-fold higher than the resting level. It is concluded that under physiological conditions (normal sodium diet) GFR and RBF are perfectly autoregulated over a wide pressure range. Renin release remains suppressed until RAP falls below a well defined threshold pressure slightly below the animal's resting systemic pressure. RBF is maintained at significantly lower pressures than GFR, indicating that autoregulation of RBF also involves postglomerular vessels.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1991

Somatization symptoms in pediatric abdominal pain patients: relation to chronicity of abdominal pain and parent somatization.

Symptoms of somatization were investigated in pediatric patients with recurrent abdominal pain (RAP) and comparison groups of patients with organic etiology for abdominal pain and well patients. Somatization scores were higher in RAP patients than well patients at the clinic visit, and higher than in either well patients or organic patients at a 3-month followup. Higher somatization scores in mothers and fathers were associated with higher somatization scores in RAP patients, but not in organic or well patients. Contrary to the findings of Ernst, Routh, and Harper (1984), chronicity of abdominal pain in RAP patients was not significantly associated with their level of somatization symptoms. Psychometric information about the Children's Somatization Inventory is presented.

Abdominal Pain↗

PubMed1996

Significance of intracranial pressure waveform analysis after head injury.

The authors have investigated the relationships between the amplitude of the ICP pulse wave, the mean values of ICP and CPP, and the outcome of 56 head injured ventilated patients. The ICP was monitored continuously using a Camino transducer (35 patients) or subdural catheter (21 patients). The mean Glasgow Coma Score was 6 (range 3-13; 5 patients had a GCS > 8 after resuscitation). Patients were grouped according to their Glasgow Outcome Score assessed at 12 months after injury. The amplitude of ICP pulse waveform was assessed using the fundamental harmonic of the pulse waveform (AMP) to avoid distortion caused by different frequency responses of the pressure transducers used in the study. Statistical analysis revealed that in patients with fatal outcome the ICP pulse amplitude increased when the mean ICP increased to 25 mmHg and then began to decrease. The upper breakpoint of the AMP-ICP relationship was not present in patients with good/moderate outcome. The moving correlation coefficient between the fundamental harmonic of ICP pulse wave and the mean ICP (RAP: R-symbol of correlation between A-amplitude and P-pressure) was introduced to describe the time-dependent changes in correlation between amplitude and mean ICP. The RAP was significantly lower in patients who died or remained in the vegetative state. In 7 patients who died from uncontrollable intracranial hypertension RAP was oscillating or decreased to 0 or negative values well before brain-stem herniation. The combination of an ICP above 20 mmHg for a period longer than 6 hours with low correlation between the amplitude and pressure (RAP < 0.5) was described as an predictive index of an unfavourable outcome.

Adolescent↗

PubMed1999

Protein kinases phosphorylating acidic ribosomal proteins from yeast cells.

Phosphorylation of ribosomal acidic proteins of Saccharomyces cerevisiae is an important mechanism regulating a number of active ribosomes. The key role in the regulatory mechanism is played by specific phosphoprotein kinases and phosphoprotein phosphatases. Three different cAMP-independent protein kinases phosphorylating acidic ribosomal proteins have been identified and characterized. The protein kinase 60S (PK60S), RAP kinase, and casein kinase type 2 (CK2). All three protein kinases phosphorylate serine residues which are localized in the C-terminal end of phosphoproteins. Synthetic peptides were used to determinate the amino acid sequence of phosphoacceptor site for PK60S. Peptide AAEESDDD derived from phosphoproteins YP1 beta/beta' and YP2 alpha turned out to be the best substrate for PK60S. A number of halogenated benzimidazoles and 2-azabenzimidazoles were tested as inhibitors of the three protein kinases. 4,5,6,7-Tetrabromo-2-azabenzimidazole inhibits phosphorylation only of these polypeptides phosphorylated by protein kinase 60S, namely YP1 beta/beta' and YP2 alpha, but not the other, YP1 alpha and YP2 beta phosphorylated by protein kinases RAP and CK2. RAP kinase has been found in an active form in the soluble fraction of S. cerevisiae. The enzyme uses ATP as a phosphate donor and is less sensitive to heparin than casein kinase 2. RAP kinase monophosphorylates the four acidic proteins. The ribosome-bound proteins are a better substrate for the enzyme. Multifunctional CK2 kinase phosphorylate all four acidic proteins. The kinase phosphorylates preferentially serine or threonine residues surrounded by cluster of acidic residues. The enzyme activity is stimulated in vitro by the presence of polylysine and inhibited by heparin.

Casein Kinase II↗

PubMed1998

Different expression of the alpha2-macroglobulin receptor/low-density lipoprotein receptor-related protein in human keratinocytes and fibroblasts.

We compared, using a combination of different immunological methods and by competitive PCR, the expression of the alpha2-macroglobulin receptor/low-density lipoprotein receptor-related protein (alpha2-M-R/LRP) in human keratinocytes and fibroblasts. This receptor has previously been found in skin only in dermal cells associated with fibroblasts and dendritic cells. For immunodetection we used mouse monoclonal antibodies against the two subunits of the receptor and against the receptor-associated protein (RAP), known as the regulatory protein of the receptor activity. The alpha2-M-R/LRP was found to be predominantly located intracellularly in keratinocytes whereas a distinct labelling of the outer membrane surface was found in fibroblasts. RAP is abundant in fibroblasts but is less expressed in keratinocytes. In frozen skin sections receptor immunoreactivity was detected in the epidermis with increased reactivity of basal keratinocytes, as well as in the dermis in association with dermal fibroblasts. By immunoprecipitation of biotinylated cell extracts, polypeptides were identified corresponding to the alpha-subunit and beta-subunit of the receptor as well as to the coprecipitating RAP. Competitive PCR revealed the presence of 67.9 and 2049.7 ag of alpha2-M-R/LRP mRNA per cell in keratinocytes and fibroblasts, respectively. The results demonstrate that both cell types express alpha-M-R/LRP mRNA and contain receptor protein as well as RAP but in different quantities and subcellular localizations.

Animals↗

PubMed2006

Photodynamic therapy with verteporfin for retinal angiomatous proliferation.

PURPOSE: The aim of this study was to evaluate the results of photodynamic therapy (PDT), using verteporfin, for subfoveal neovascular age-related macular degeneration (ARMD) with retinal angiomatous proliferation (RAP) with pigment epithelial detachment (PED) and/or choroidal neovascularization (CNV). METHODS: In this non-comparative, consecutive, interventional, case series, the data on 21 eyes (19 with stage 2 and two with stage 3 RAP) of 20 patients were reviewed. Serous PED occupied more than 50% of the lesion in 19 eyes. PDT was performed as per TAP protocol. Biomicroscopy and fluorescein and indocyanine-green angiography were performed to evaluate anatomical results and need for retreatment. Changes from baseline in best-corrected visual acuity (BCVA), and complications, were assessed. RESULTS: A mean of 3.5+/-0.9 treatments was performed. After 13.7+/-2.2 months, mean BCVA decreased from 20/80 to 20/174 (P=0.0063). In six eyes (28.6%) BCVA remained stable, whereas in 15 eyes (71.5%) it decreased. Occlusion of RAP and flattening of PED was observed in three (14.2%) eyes, conversion to disciform lesion in one (4.7%), and persistence of PED in 11 eyes (52.3%). One eye (4.7%) evolved to haemorrhagic PED, and one (4.7%) toward stage 3 RAP. A tear in the retinal pigment epithelium (RPE) was observed in four eyes (19%). Eleven (52.3%) showed progression of leakage, six moderate leakage (28.6%), and three (14.2%) absence of leakage. CONCLUSIONS: Timely PDT with verteporfin in the early stages in eyes with smaller lesions has the potential for a beneficial effect on vision, whereas it might worsen the natural course of larger lesions, with most eyes undergoing enlargement, disciform transformation or RPE tear.

Aged↗

PubMed1996

Up-regulation of the low density lipoprotein receptor-related protein by dexamethasone in HepG2 cells.

Dexamethasone has been shown to decrease the expression of the low density lipoprotein (LDL) receptor, but its effect on other members of the LDL receptor family is not known. We studied the effect of dexamethasone in HepG2 cells on the expression of the LDL receptor family members using radiolabeled receptor associated protein (RAP) which binds to all the members of the family. Treatment of HepG2 cells with increasing concentrations of dexamethasone resulted in a 2-fold increase in the binding and degradation of RAP. To identify the receptor responsible for the increased binding and degradation of RAP, we used specific ligands. For LDL receptor, we used LDL itself. For the LDL receptor-related protein/alpha 2-macroglobulin receptor, we used activated alpha 2-macroglobulin. The binding of LDL to HepG2 cells was decreased, whereas binding and degradation of activated alpha 2-macroglobulin was increased by 2-fold suggesting that dexamethasone increased LRP expression. Increased LRP expression was positively correlated with the increase in the steady-state levels and transcript numbers of the LRP mRNA; no changes in RAP or gamma-actin mRNA levels were observed. Increased mRNA levels were not due to an increased rate of transcription of the gene as assessed by nuclear run-on experiments. These studies indicate that dexamethasone increases cell-surface LRP activity in HepG2 cells by increasing the steady state mRNA levels and suggest that post-transcriptional mechanisms play a role in controlling LRP mRNA levels.

Cell Line↗