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PubMed2004

Thrombin generation: phenotypic quantitation.

An individual's ability to generate thrombin following tissue factor stimulus was evaluated in 13 healthy male donors in a 6-month study. Thrombin generation in whole blood collected by phlebotomy, contact pathway suppressed by the presence of 100 micro g mL-1 corn trypsin inhibitor, was initiated by the addition of 5 pm tissue factor/10 nm phospholipid. Reactions were quenched at 20 min by the addition of an ethylenediaminetetraacetic acid (EDTA), benzamidine, FPRck cocktail. Thrombin generation was determined by an ELISA for thrombin-antithrombin III (TAT) complex formation. Results showed that the levels of TAT observed varied from 245 to 775 nm. Thrombin production was consistent within each individual, CVi = 11.6%, but varied significantly within the group, CVg = 25.2%, and correlated inversely with an individual's clotting time (r = - 0.54, P = 0.07). No correlations were individually observed between TAT and C-reactive protein, antithrombin III, factors II, V, VII, VIII, IX and X, fibrinogen and prothrombin time. However, computer simulations, which integrated each individual's coagulation factor levels using the Speed Rx method (Hockin et al., J Biol Chem 2002; 277: 18322), predicted maximum active thrombin levels (ranging from calculated values of 220-500 nm) consistent with the empirically determined values. Overall, these data suggest that thrombin generated in whole blood exclusively by tissue factor stimulation can be used as an integrative phenotypic marker to determine an individual's response to a tissue factor challenge.

Adult↗
PubMed1991

Characterization of cytokines present in middle ear effusions.

Retention of inflammatory mediators and cells in the middle ear cleft during chronic otitis media with effusion (COME), results in ongoing inflammation with the potential for pathologic changes and hearing loss. Cytokines are glycoproteins produced by macrophages and other cells. Activities of cytokines include fever production, osteoclast, fibroblast, phagocyte and cytotoxic cell activation, regulation of antibody formation, and inhibition of cartilage, bone and endothelial cell growth. Using enzyme-linked immunospecific assays we measured levels of six cytokines in middle ear effusions (MEE) from children with COME. Significant levels of four cytokines: interleukin-1-beta (greater than 50 pg/ml), interleukin-2 (greater than 300 pg/ml), tumor necrosis factor-alpha (greater than 40 pg/ml), and gamma-interferon (greater than 6.25 pg/ml) were found in 51%, 54%, 63%, and 19% of MEE, respectively. In contrast, levels of a fifth cytokine, granulocyte-macrophage colony-stimulating factor, and a sixth cytokine, interleukin-4, were undetectable. Age was observed to have a significant effect on the levels of specific cytokines. Interleukin-1 (IL-1) correlated inversely (P less than .02) with age such that the younger the child, the higher the level of IL-1 in MEE. Tumor necrosis factor-alpha (TNF) correlated directly (P less than .005) with age such that the older the child, the higher the level of TNF in MEE. Children undergoing tympanostomy on multiple occasions had average MEE TNF levels (234.2 +/- 109.1 pg/mg total protein) that were nearly 14 times higher (P less than .005) than those from children undergoing their first tympanostomy (16.9 +/- 3.0 pg/mg total protein). Thus IL-1 correlated with the early stages of COME, while TNF correlated with persistence of disease. The presence of these cytokines in MEE may be responsible for the mucosal damage, bone erosion, fibrosis, and resulting hearing loss seen in some cases of COME.

Aging↗
PubMed1991

Octreotide stimulates insulin-like growth factor binding protein-1 (IGFBP-1) levels in acromegaly.

Insulin-like growth factors (IGFs) circulate in a complexed state with several binding proteins (BPs). Of these, IGFBP-1 is regulated by hormonal and nutritional factors. The somatostatin analogue, octreotide, has been used to effectively control hypersomaototropism in acromegaly. IGFBP-1 levels were measured by RIA in 17 acromegalic patients receiving octreotide. Serum hormone sampling was conducted hourly for 8 hr periods. Among 13 octreotide responders, mean pre-treatment basal GH, IGF-1, and IGFBP-1 levels were 19 +/- 5 micrograms/L, 1021 +/- 168 micrograms/L, and 36 +/- 8 micrograms/L respectively. One month following octreotide treatment, an acute subcutaneous injection (100 micrograms) maximally attenuated GH to 3 +/- 0.6 microgram/L (18% of control, P less than 0.03) and IGF-1 to 467 +/- 75 micrograms/L (46% of control, P less than 0.008) after 4 hrs. IGFBP-1 levels, however, were stimulated to 95 +/- 16 micrograms/L (297% of control, P less than 0.003) during the same time period. A significant increase in IGFBP-1 levels occurred within 2 hrs (158% of baseline, P less than 0.03), and was sustained until the 7th hr following injection. Insulin, a known suppressor of IGFBP-1, did not change during this time. Among the 4 octreotide non-responders, mean basal IGFBP-1 levels were 42 +/- 4 micrograms/L, and 4 hrs following octreotide administration IGFBP-1 was 40 +/- 7 micrograms/L. Octreotide induced a dynamic inverse relationship between circulating GH and IGFBP-1 levels (r = -0.73, P less than 0.001). The absence of IGFBP-1 changes in octreotide non-responders and the non-suppression of insulin in octreotide responsive patients, suggest a direct GH-mediated mechanism of IGFBP-1 regulation in octreotide treated patients with acromegaly. IGFBP-1 may be another useful marker in evaluating the response of acromegaly to octreotide treatment in patients who experience clinical benefit but equivocal GH and IGF-1 attenuation.

Acromegaly↗
PubMed1998

Induction of tissue inhibitor of metalloproteinases-3 is a delayed early cellular response to hepatocyte growth factor.

Hepatocyte growth factor (HGF) stimulates mitogenic, motogenic, and morphogenic responses in various cell types. We analysed HGF-responsive cells by differential display PCR to identify HGF-induced genes that mediate these biological events. One of the genes identified encoded a member of the tissue inhibitor of metalloproteinases (TIMP) family, TIMP-3. HGF transiently induced TIMP-3 mRNA in keratinocytes as well as kidney and mammary epithelial cells maximally between 4 and 6 h post-stimulation. Increased TIMP-3 protein secretion returned to basal levels within 18 h, while the expression of gelatinases A and B remained unchanged, suggesting that temporary suppression of matrix degradation is a delayed early response to HGF. Ectopic overexpression of TIMP-3 in cultured leiomyosarcoma cells conferred an epithelial morphology, reduced cell growth rate, anchorage-independent growth, and matrix invasion in vitro. Antisense suppression of TIMP-3 was associated with a scattered, fibroblastic cell morphology, as well as enhanced proliferation, anchorage-independent growth, and matrix invasion. A survey of tumor cell lines revealed an inverse relationship between metastatic potential and TIMP-3 expression level. These data suggest that early, transient TIMP-3 expression mediates specific HGF-induced phenotypic changes, and that loss of TIMP-3 expression may enhance the invasion potential of certain tumors.

3T3 Cells↗
PubMed1993

PilS and PilR, a two-component transcriptional regulatory system controlling expression of type 4 fimbriae in Pseudomonas aeruginosa.

Transposon mutagenesis was used to identify genes necessary for the expression of Pseudomonas aeruginosa type 4 fimbriae. In a library of 12,700 mutants, 147 were observed to have lost the spreading colony morphology associated with the presence of functional fimbriae. Of these, 28 had also acquired resistance to the fimbrial-specific bacteriophage PO4. The mutations conferring this phage resistance were found to have occurred at at least six different loci, including the three that had been previously shown to be required for fimbrial biosynthesis or function: the structural subunit (pilA) and adjacent genes (pilB,C,D), the twitching motility gene (pilT), and the sigma 54 RNA polymerase initiation factor gene (rpoN). One novel group of phage-resistant mutants was identified in which the transposon had inserted near sequences that cross-hybridized to an oligonucleotide probe designed against conserved domains in regulators of RpoN-dependent promoters. These mutants had no detectable transcription of pilA and did not produce fimbriae. A probe derived from inverse polymerase chain reaction was used to isolate the corresponding wild-type sequences from a P. aeruginosa PAO cosmid reference library, and two adjacent genes affected by transposon insertions, pilS and pilR, were located and sequenced. These genes were shown to be capable of complementing the corresponding mutants, both at the level of restoring the phenotypes associated with functional fimbriae and by the restoration of pilA transcription. The pilSR operon was physically mapped to Spel fragment 5 (corresponding to about 72-75/0 min on the genetic map), and shown to be located approximately 25 kb from pilA-D. PilS and PilR clearly belong to the family of two-component transcriptional regulatory systems which have been described in many bacterial species. PilS is predicted to be a sensor protein which when stimulated by the appropriate environmental signals activates PilR through kinase activity. PilR then activates transcription of pilA, probably by interacting with RNA polymerase containing RpoN. The identification of pilS and pilR makes possible a more thorough examination of the signal transduction systems controlling expression of virulence factors in P. aeruginosa.

Amino Acid Sequence↗
PubMed1986

Purification and properties of the DNA invertase gin encoded by bacteriophage Mu.

The host range of bacteriophage Mu is regulated through an invertible segment. Inversion requires the presence of two properly oriented recombination sites and a recombinational enhancer sis. The reaction is catalyzed by the Mu-encoded DNA invertase Gin and a host factor termed factors for inversion stimulation (FISs). We present a novel purification scheme for Gin. Purified Gin alone catalyzes the inversion reaction at very low efficiency recombining less than 0.8% of substrate molecules. When supplemented with FIS substrates containing the recombinational enhancer are recombined efficiently. Stoichiometric amounts of Gin are required for recombination.

Cations, Divalent↗
PubMed2003

Sp1 inhibits proliferation and induces apoptosis in vascular smooth muscle cells by repressing p21WAF1/Cip1 transcription and cyclin D1-Cdk4-p21WAF1/Cip1 complex formation.

Atherosclerosis and restenosis are common vascular disorders that involve excess proliferation of smooth muscle cells (SMCs) in the artery wall. In this study we demonstrate the anti-mitogenic, pro-apoptotic role of the zinc finger transcription factor Sp1 in vascular SMCs and define the underlying molecular mechanism via its capacity to repress the expression of the cyclin-dependent kinase inhibitor p21WAF1/Cip1 at the level of transcription, mRNA, and protein. SMC proliferation inducible by a dominant-negative mutant form of Sp1 was abrogated by antisense strategies targeting p21WAF1/Cip1. Conversely, antisense p21WAF1/Cip1 induced apoptosis in SMCs overexpressing dominant-negative-Sp1. p21WAF1/Cip1 overexpression alone stimulated proliferation and inhibited apoptosis. Sp1 down-regulated p21WAF1/Cip1 expression in SMCs. Sp1 blocked assembly of cyclin D1-Cdk4-p21WAF1/Cip1 complex formation whose integrity is critical for G1->S transition. Moreover, Rb phosphorylation, which lies immediately downstream of the cyclin D1-Cdk4-p21WAF1/Cip1 complex, was blocked either by Sp1 overexpression or antisense p21WAF1/Cip1. These findings, using complementary approaches, demonstrate the inverse relationship between Sp1 and p21WAF1/Cip1 in SMCs and the capacity of Sp1 to regulate SMC proliferation and apoptosis via its repression of p21WAF1/Cip1.

Animals↗
PubMed2002

Effect of light and protein phosphorylation on photoreceptor rod outer segment acyltransferase activity.

Rod outer segments (ROS) exhibit high acyltransferase (AT) activity, the preferred substrate of which being lysophosphatidylcholine. To study factors possibly regulating ROS AT activity purified ROS membranes were assayed under conditions under which protein kinase C (PKC), cAMP-dependent protein kinase (PKA), and phosphatases were stimulated or inhibited. PKC activation produced a significant increase in the acylation of phosphatidylethanolamine (PE) and phosphatidylinositol (PI) with oleate, it inhibited phosphatidylcholine (PC) acylation, and phosphatidylserine (PS) and phosphatidic acid (PA) acylation remained unchanged. ROS PKA activation resulted in increased oleate incorporation into PS and PI while the acylation of PC, PE, and PA remained unchanged. Inhibition of ROS PKC or PKA produced, as a general trait, inverse effects with respect to those observed under kinase-stimulatory conditions. ROS phosphatase 2A was inhibited by using okadaic acid, and the changes observed in AT activity are described. These findings suggest that changes in ROS protein phosphorylation produce specific changes in AT activity depending on the phospholipid substrate. The effect of light on AT activity in ROS membranes was also studied and it is reported that acylation in these membranes remains unchanged independent of the illumination condition used.

Acyltransferases↗
PubMed2005

Stimulation of microglial metabotropic glutamate receptor mGlu2 triggers tumor necrosis factor alpha-induced neurotoxicity in concert with microglial-derived Fas ligand.

Activated microglia may be detrimental to neuronal survival in a number of neurodegenerative diseases. Thus, strategies that reduce microglial neurotoxicity may have therapeutic benefit. Stimulation of group II metabotropic glutamate (mGlu) receptors on rat primary microglia with the specific group II agonist 2S,2'R,3'R-2-(2',3'-dicarboxy-cyclopropyl)glycine for 24 h induced microglial activation and resulted in a neurotoxic microglial phenotype. These effects were attributable to preferential mGlu2 stimulation, because N-acetyl-L-aspartyl-L-glutamate, a specific mGlu3 agonist, did not induce microglial activation or neurotoxicity. Stimulation of microglial mGlu2 but not mGlu3 induced caspase-3 activation in cerebellar granule neurons in culture, using microglial-conditioned media as well as cocultures. Stimulation of microglial mGlu2 induced tumor necrosis factor-alpha (TNFalpha) release, which contributed to microglial neurotoxicity mediated via neuronal TNF receptor 1 and caspase-3 activation. Stimulation of microglial group I or III mGlu receptors did not induce TNFalpha release. TNFalpha was only neurotoxic in the presence of microglia or microglial-conditioned medium. The toxicity of TNFalpha could be prevented by coexposure of neurons to conditioned medium from microglia stimulated by the specific group III agonist L-2-amino-4-phosphono-butyric acid. The neurotoxicity of TNFalpha derived from mGlu2-stimulated microglia was potentiated by microglial-derived Fas ligand (FasL), the death receptor ligand. FasL was constitutively expressed in microglia and shed after mGlu2 stimulation. Our data suggest that selective and inverse modulation of microglial mGlu2 and mGlu3 may prove a therapeutic target in neuroinflammatory diseases such as Alzheimer's disease and multiple sclerosis.

Animals↗
PubMed2005

De novo synthesis of diacylglycerol in endothelium may mediate the association between PAI-1 and the insulin resistance syndrome.

Increased free fatty acid flux, giving rise to increased de novo synthesis of diacylglycerol (DAG) and activation of protein kinase C (PKC) in vascular endothelium, may be largely responsible for the endotheliopathy and increased vascular risk associated with insulin resistance syndrome. This mechanism may also mediate, in large part, the increase in plasminogen activator inhibitor-1 (PAI-1) observed in this syndrome. PKC activation promotes transcription of PAI-1 in endothelial cells and other tissues, apparently by boosting the activity of Sp1 transcription factors that bind to the PAI-1 promoter. Plasma PAI-1 correlates inversely with the ability of insulin infusion to suppress free fatty acid levels. Moreover, infusion of triglycerides with heparin - inducing a marked increase in free fatty acids - has been shown to induce a rapid increase in plasma PAI-1. Alternatively, hyperinsulinemia and hypertriglyceridemia have been suggested as mediators of PAI-1 excess in insulin resistance, inasmuch as insulin and VLDL can stimulate PAI-1 production in cell cultures. However, plasma PAI-1 tends to decline in response to hyperinsulinemic clamps and insulin treatment of type 2 diabetes, and gemfibrozil treatment of hypertriglyceridemia does not decrease PAI-1 - suggesting that elevations of insulin or triglycerides are not likely to mediate PAI-1 excess in vivo. Hypertrophied adipose mass can secrete PAI-1, and is likely to contribute to the plasma PAI-1 pool in obese insulin-resistant subjects, but current evidence suggests that this is not likely to be the primary source of the elevated plasma PAI-1 in insulin resistance syndrome. Plasma PAI-1 can be decreased in insulin resistant subjects by improving adipocyte insulin sensitivity (with weight loss and thiazolidinediones), by consuming a very-low-fat diet that minimizes postprandial free fatty acid flux, and by administering activators of AMP-activated kinase (e.g., metformin), which can be expected to lessen tissue DAG synthesis.

Cardiovascular System↗
PubMedDate not supplied

[Proliferative response and suppressor activity of lymphocytes in candidiasis].

In 14 practically healthy donors, 22 patients with chronic candidiasis of the skin and mucosa (CCSM) and 14 patients with chronic candidal vulvovaginitis (CCW) immunoregulating factors synthesized by peripheral blood lymphocytes under the conditions of in vitro induction of suppressor cells were studied in comparison with the proliferative response to PHA and Candida albicans cytoplasmic protein. In practically healthy donors the level of lymphocyte response to mitogen coincided with the presence of the inhibiting activity of supernatants. In a more severe form of Candida infection (CCSM) the proliferative reaction of lymphocytes to both PHA and C.albicans antigen was weakened or even inhibited. The level of the proliferative response of lymphocytes was inversely proportional to the immunoregulating activity of cells, nonstimulated and stimulated with ConA and C.albicans cytoplasmic protein. In CCW lymphocytes exhibited good proliferative response to T-mitogen, occurring in combination with weak reaction, or no reaction at all, to C.albicans antigen. A decrease in the level of spontaneous blast transformation was accompanied by an increase in spontaneous suppressor activity.

Antigens, Fungal↗
PubMed1992

Neutrophil activation associated with increased neutrophil acyloxyacyl hydrolase activity during inflammation in cattle.

Acyloxyacyl hydrolase (AOAH) is a lysosomal enzyme found in neutrophils and macrophages that acts to partially deacylate the lipid-A component of the endotoxin of gram-negative bacteria rendering it less toxic, yet maintaining much of its immunostimulatory potential. We have found that the activity of neutrophil AOAH per cell increased during localized inflammation. The purpose of this study was to determine the mechanism(s) responsible for these increases in neutrophil AOAH activity. Because changes in neutrophil maturity commonly are associated with inflammation, intravascular infusion of purified gram-negative bacterial lipopolysaccharide and SC injection of bovine recombinant granulocyte colony-stimulating factor was used to induce large numbers of circulating immature neutrophils. Immature neutrophils were found to have AOAH activity equal to that of mature cells; however, when neutrophils were stimulated in vitro with known activators, AOAH activity of activated cells was more than that of unstimulated cells. The increase in AOAH activity was inversely related to prestimulation activity. Increases in AOAH activity after neutrophil activation were not a result of de novo synthesis of the enzyme, because cycloheximide did not prevent activation-induced increases in activity.

Animals↗
PubMed2004

Invasive M1T1 group A Streptococcus undergoes a phase-shift in vivo to prevent proteolytic degradation of multiple virulence factors by SpeB.

A globally disseminated strain of M1T1 group A Streptococcus (GAS) has been associated with severe infections in humans including necrotizing fasciitis and toxic shock syndrome. Recent clinicoepidemiologic data showed a striking inverse relationship between disease severity and the degree to which M1T1 GAS express the streptococcal cysteine protease, SpeB. Electrophoretic 2-D gel analysis of the secreted M1T1 proteome, coupled with MALDI-TOF mass spectroscopy, revealed that expression of active SpeB caused the degradation of the vast majority of secreted GAS proteins, including several known virulence factors. Injection of a SpeB+/SpeA- M1T1 GAS strain into a murine subcutanous chamber model of infection selected for a stable phase-shift to a SpeB-/SpeA+ phenotype that expressed a full repertoire of secreted proteins and possessed enhanced lymphocyte-stimulating capacity. The proteome of the SpeB-in vivo phase-shift form closely matched the proteome of an isogenic speB gene deletion mutant of the original M1T1 isolate. The absence or the inactivation of SpeB allowed proteomic identification of proteins in this M1T1 clone that are not present in the previously sequenced M1 genome including SpeA and another bacteriophage-encoded novel streptodornase allele. Further proteomic analysis of the M1T1 SpeB+ and SpeB- phase-shift forms in the presence of a cysteine protease inhibitor demonstrated differences in the expression of several proteins, including the in vivo upregulation of SpeA, which occurred independently of SpeB inactivation.

Animals↗
PubMed1998

Induction of human immunodeficiency virus type 1 replication in human glial cells after proinflammatory cytokines stimulation: effect of IFNgamma, IL1beta, and TNFalpha on differentiation and chemokine production in glial cells.

Although evidence for human immunodeficiency virus 1 (HIV-1) presence in the central nervous system (CNS) of infected patients is well established, the intensity of viral replication within the brain is not usually known. In vitro, human embryonic microglial cells internalized HIV-1 through a CD4-dependent pathway but were not permissive to viral replication. We observed that HIV replication was induced when CNS cell cultures were stimulated for 14 days by a combination of proinflammatory cytokines including IFNgamma, IL1beta, and TNFalpha. After long-term cytokine stimulation, morphologically differentiated glial cells appeared, in which HIV-1 tat antigen was detected after infection. Thus, variations in the stage of maturation/activation of CNS cells under inflammatory conditions probably play a major role in facilitating massive production of HIV-1. We then studied the effect of prolonged cytokine stimulation on the secretion of inflammatory mediators by glial cells. An early increased secretion of prostaglandin F2alpha and chemokines (RANTES>>MIP-1alpha>>MIP-1beta) was observed, due to both microglia and astrocytes. In contrast to persistent PGF2alpha production, an extinction of RANTES and MIP-1beta but not of MIP-1alpha secretion occurred during the 14 days of stimulation and was inversely correlated with the ability of glial cells to replicate HIV-1. The study of the secretory factors produced in response to a persistent inflammation could provide a better understanding of the modulation of HIV replication in glial cells.

Cell Differentiation↗
PubMed1993

Lrp stimulates phase variation of type 1 fimbriation in Escherichia coli K-12.

The phase variation of type 1 fimbriation in Escherichia coli is associated with the inversion of a short DNA element. This element (switch) acts in cis to control transcription of fimA, the major fimbrial subunit gene. Thus, fimA is transcribed when the switch is in one orientation (the on orientation) but not the other (the off orientation). The fim inversion requires either fimB (on-to-off or off-to-on inversion) or fimE (on-to-off inversion only), as well as integration host factor, and is also influenced by the abundant DNA-binding protein H-NS. Here we report that an additional gene, lrp, a factor known to influence the expression of both Pap and K99 fimbriae, is also required for normal activity of the fim switch. The frequencies of both fimB-promoted and fimE-promoted inversions, and consequently the phase variation of type 1 fimbriation, are lower in lrp mutants. Lrp affects slightly the transcription of both fimB (which is increased) and fimE (which is decreased). We believe that these alterations in fimB and fimE transcription alone are unlikely to account for the sharp reduction in switching found in lrp mutants.

Bacterial Proteins↗
PubMed2003

Decreased total antioxidant status and increased oxidative stress in women with polycystic ovary syndrome may contribute to the risk of cardiovascular disease.

OBJECTIVE: To determine oxidative stress by the level of protein carbonyls and total antioxidant status (TAOS), and whether oxidative stress is associated with increased risk of cardiovascular disease in women with polycystic ovary syndrome (PCOS). DESIGN: Controlled clinical study. SETTING: University hospital. PATIENT(S): Thirty women with PCOS and 31 healthy control women. INTERVENTION(S): Biometric measures and blood samples collection. MAIN OUTCOME MEASURE(S): C-reactive protein (CRP), lipid fractions, glucose, protein carbonyls, insulin, and other hormone (gonadotropins, androgens) levels and TAOS were measured. The estimate of insulin resistance was calculated by homeostasis model assessment (HOMA-R). RESULT(S): The women with PCOS had significantly higher serum fasting insulin, CRP, protein carbonyl levels, HOMA-R, LH levels, and LH/FSH ratios than healthy women. However, TAOS was significantly lower in women with PCOS. TAOS was negatively correlated with fasting insulin, HOMA-R, CRP, and protein carbonyls. Fasting insulin was positively correlated with protein carbonyls. High density lipoprotein (HDL) was inversely associated with fasting insulin, HOMA-R, and protein carbonyls. CONCLUSION(S): Increased oxidative stress and decreased antioxidant capacity may contribute to the increased risk of cardiovascular disease in women with PCOS, in addition to known risk factors such as insulin resistance, hypertension, central obesity, and dyslipidemia.

Adolescent↗
PubMed1994

Growth factors and decidualization in vitro.

Growth factors are believed to act as local regulators of endometrial cyclic activity, but there is limited information on their regulation of decidual differentiation and function. Cell cultures of human endometrial stroma treated with progesterone (P) undergo morphologic, proliferative and secretory changes characteristic of decidualizing endometrium. In the presence of P, different growth factors can stimulate cell proliferation, but decidual differentiation is induced specifically by EGF, as shown by the production of prolactin (PRL), fibronectin, laminin, and insulin-like growth factor binding protein 1 (IGFBP-1). The present study investigates the effects of the insulin-like growth factors (IGF-I, IGF-II) on decidualization in vitro, as indicated by a P-dependent growth response and by the secretion of PRL and IGFBP-1. IGFs were required together with EGF and P to stimulate stromal cell proliferation. In contrast, PRL (38 +/- 4 ng/day/10(6) cells) and IGFBP-1 (26 +/- 3 micrograms/day/10(6) cells) were secreted by in vitro decidualized cells in the absence of exogenous IGFs. However, IGFs regulated both IGFBP-1 and PRL secretion in a dose-dependent biphasic manner. Stimulation of IGFBP-1 (200-250%) and PRL (243-324%) peaked at 1 ng/ml for IGF-I, and 10 ng/ml for IGF-II, followed by inhibition at higher peptide concentrations (ED50s 3 and 30 ng/ml, respectively). Maximal physiological doses (100 ng/ml) of IGF-I and IGF-II virtually abolished IGFBP-1 secretion (1% and 2% of basal levels, respectively), but did not cause total suppression of PRL secretion (8% and 22% of basal levels). IGF-induced mitogenesis was inversely correlated with endogenous IGFBP-1 levels in in vitro decidualized stromal cultures. Our studies show that growth factor interactions regulate decidual function, and that specific cellular functions associated with the decidual response are differentially regulated by growth factor interactions. Our findings support a role for the IGF system in autocrine/paracrine interactions during decidualization and early pregnancy. It is speculated that IGF-II may constitute one of the embryonic signaling mechanisms during early postimplantation stages.

Carrier Proteins↗
PubMed1994

The cellular concentration of the sigma S subunit of RNA polymerase in Escherichia coli is controlled at the levels of transcription, translation, and protein stability.

The second vegetative sigma factor sigma S (encoded by the rpoS gene) is the master regulator in a complex regulatory network that governs the expression of many stationary phase-induced and osmotically regulated genes in Escherichia coli. Using a combination of gene-fusion technology and quantitative immunoblot, pulse-labeling, and immunoprecipitation analyses, we demonstrate here that rpoS/sigma S expression is not only transcriptionally controlled, but is also extensively regulated at the levels of translation and protein stability. rpoS transcription is inversely correlated with growth rate and is negatively controlled by cAMP-CRP. In complex medium rpoS transcription is stimulated during entry into stationary phase, whereas in minimal media, it is not significantly induced. rpoS translation is stimulated during transition into stationary phase as well as by an increase in medium osmolarity. A model involving mRNA secondary structure is suggested for this novel type of post-transcriptional growth phase-dependent and osmotic regulation. Furthermore, sigma S is a highly unstable protein in exponentially growing cells (with a half-life of 1.4 min), that is stabilized at the onset of starvation. When cells are grown in minimal glucose medium, translational induction and sigma S stabilization occur in a temporal order with the former being stimulated already in late exponential phase and the latter taking place at the onset of starvation. Although sigma S does not control its own transcription, it is apparently indirectly involved in a negative feedback control that operates on the post-transcriptional level. Our analysis also indicates that at least five different signals [cAMP, a growth rate-related signal (ppGpp?), a cell density signal, an osmotic signal, and a starvation signal] are involved in the control of all these processes that regulate rpoS/sigma S expression.

Base Sequence↗