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PubMed1995

The developing rat lung fibroblast and alveolar type II cell actively recruit surfactant phospholipid substrate.

Timely, adequate production of pulmonary surfactant is critical for survival at birth. This process is dependent on both maternal nutrition and glucocorticoids. Fetal rat lung lipofibroblast triglyceride accumulation is saturable, temperature-dependent and stimulated by glucocorticoids and cyclic AMP in primary cell culture. Spontaneous triglyceride uptake by fibroblasts increases ninefold between 17 and 21 days (= term) gestation and is stimulated 30-80% by exogenous glucocorticoid treatment. Coculture of Type II cells with fibroblasts preloaded with 3H-trioleate and increasing amounts of triglyceride results in a concomitant increase in saturated phosphatidylcholine (SPC) synthesized by Type II cells. Dexamethasone stimulates mobilization of fibroblast triglyceride incorporation into Type II cell-SPC by 36-40%. The hormonally regulated uptake and mobilization of triglyceride suggest active recruitment of surfactant phospholipid substrate by both alveolar connective tissue and epithelial cells.

Animals↗
PubMed2003

The AF-1 domain of the orphan nuclear receptor NOR-1 mediates trans-activation, coactivator recruitment, and activation by the purine anti-metabolite 6-mercaptopurine.

NOR-1/NR4A3 is an "orphan member" of the nuclear hormone receptor superfamily. NOR-1 and its close relatives Nurr1 and Nur77 are members of the NR4A subgroup of nuclear receptors. Members of the NR4A subgroup are induced through multiple signal transduction pathways. They have been implicated in cell proliferation, differentiation, T-cell apoptosis, chondrosarcomas, neurological disorders, inflammation, and atherogenesis. However, the mechanism of transcriptional activation, coactivator recruitment, and agonist-mediated activation remain obscure. Hence, we examined the molecular basis of NOR-1-mediated activation. We observed that NOR-1 trans-activates gene expression in a cell- and target-specific manner; moreover, it operates in an activation function (AF)-1-dependent manner. The N-terminal AF-1 domain delimited to between amino acids 1 and 112, preferentially recruits the steroid receptor coactivator (SRC). Furthermore, SRC-2 modulates the activity of the AF-1 domain but not the C-terminal ligand binding domain (LBD). Homology modeling indicated that the NOR-1 LBD was substantially different from that of hRORbeta, a closely related AF-2-dependent receptor. In particular, the hydrophobic cleft characteristic of nuclear receptors was replaced with a very hydrophilic surface with a distinct topology. This observation may account for the inability of this nuclear receptor LBD to efficiently mediate cofactor recruitment and transcriptional activation. In contrast, the N-terminal AF-1 is necessary for cofactor recruitment and can independently conscript coactivators. Finally, we demonstrate that the purine anti-metabolite 6-mercaptopurine, a widely used antineoplastic and anti-inflammatory drug, activates NOR-1 in an AF-1-dependent manner. Additional 6-mercaptopurine analogs all efficiently activated NOR-1, suggesting that the signaling pathways that modulate proliferation via inhibition of de novo purine and/or nucleic acid biosynthesis are involved in the regulation NR4A activity. We hypothesize that the NR4A subgroup mediates the genotoxic stress response and suggest that this subgroup may function as sensors that respond to genotoxicity.

Animals↗
PubMed2003

Molecular determinants of the balance between co-repressor and co-activator recruitment to the retinoic acid receptor.

The repressive and activating states of nuclear hormone receptors are achieved through the recruitment of cofactor proteins. The binding of co-repressors and co-activators is believed to be mutually exclusive and principally regulated by ligand binding. To understand the molecular determinants of the switch induced by ligand in the retinoic acid receptor and in particular the intrinsic role of the ligand binding domain (LBD) in cofactor binding and release, we carried out extensive mutational analysis of surface residues of the LBD. As seen previously we found that co-repressor and co-activator molecules bind to overlapping docking sites on the surface of the retinoic acid receptor alpha LBD. Perturbation of this surface impaired both co-activator and co-repressor association resulting in a transcriptionally inert receptor. Unexpectedly mutation of two residues, Trp-225 and Ala-392, which lie outside the docking site, had opposite effects on co-activator and co-repressor binding. W225A was a constitutive repressor that failed to bind co-activator and exhibited an increased, and ligand-insensitive, interaction with co-repressor. A392R, on the other hand, had reduced affinity for co-repressors and increased affinity for co-activators and behaved as a constitutive, but still ligand-inducible, activator. Analysis of known structures showed that these mutations lie in the proximity of helix 12 (H12), and their effects are likely to be the result of perturbations in the behavior of H12. These data suggest that residues in the close vicinity of H12 regulate cofactor affinity and determine the basal activity of receptors.

Alanine↗
PubMed2001

Recruitment, activation and retention of caspases-9 and -3 by Apaf-1 apoptosome and associated XIAP complexes.

During apoptosis, release of cytochrome c initiates dATP-dependent oligomerization of Apaf-1 and formation of the apoptosome. In a cell-free system, we have addressed the order in which apical and effector caspases, caspases-9 and -3, respectively, are recruited to, activated and retained within the apoptosome. We propose a multi-step process, whereby catalytically active processed or unprocessed caspase-9 initially binds the Apaf-1 apoptosome in cytochrome c/dATP-activated lysates and consequently recruits caspase-3 via an interaction between the active site cysteine (C287) in caspase-9 and a critical aspartate (D175) in caspase-3. We demonstrate that XIAP, an inhibitor-of-apoptosis protein, is normally present in high molecular weight complexes in unactivated cell lysates, but directly interacts with the apoptosome in cytochrome c/dATP-activated lysates. XIAP associates with oligomerized Apaf-1 and/or processed caspase-9 and influences the activation of caspase-3, but also binds activated caspase-3 produced within the apoptosome and sequesters it within the complex. Thus, XIAP may regulate cell death by inhibiting the activation of caspase-3 within the apoptosome and by preventing release of active caspase-3 from the complex.

Apoptosis↗
PubMed2003

HIV Gag mimics the Tsg101-recruiting activity of the human Hrs protein.

The HIV-1 Gag protein recruits the cellular factor Tsg101 to facilitate the final stages of virus budding. A conserved P(S/T)AP tetrapeptide motif within Gag (the "late domain") binds directly to the NH2-terminal ubiquitin E2 variant (UEV) domain of Tsg101. In the cell, Tsg101 is required for biogenesis of vesicles that bud into the lumen of late endosomal compartments called multivesicular bodies (MVBs). However, the mechanism by which Tsg101 is recruited from the cytoplasm onto the endosomal membrane has not been known. Now, we report that Tsg101 binds the COOH-terminal region of the endosomal protein hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs; residues 222-777). This interaction is mediated, in part, by binding of the Tsg101 UEV domain to the Hrs 348PSAP351 motif. Importantly, Hrs222-777 can recruit Tsg101 and rescue the budding of virus-like Gag particles that are missing native late domains. These observations indicate that Hrs normally functions to recruit Tsg101 to the endosomal membrane. HIV-1 Gag apparently mimics this Hrs activity, and thereby usurps Tsg101 and other components of the MVB vesicle fission machinery to facilitate viral budding.

Cell Line↗
PubMed1998

Active recruitment of sigma54-RNA polymerase to the Pu promoter of Pseudomonas putida: role of IHF and alphaCTD.

The sequence elements determining the binding of the sigma54-containing RNA polymerase (sigma54-RNAP) to the Pu promoter of Pseudomonas putida have been examined. Contrary to previous results in related systems, we show that the integration host factor (IHF) binding stimulates the recruitment of the enzyme to the -12/-24 sequence motifs. Such a recruitment, which is fully independent of the activator of the system, XylR, requires the interaction of the C-terminal domain of the alpha subunit of RNAP with specific DNA sequences upstream of the IHF site which are reminiscent of the UP elements in sigma70 promoters. Our data show that this interaction is mainly brought about by the distinct geometry of the promoter region caused by IHF binding and the ensuing DNA bending. These results support the view that binding of sigma54-RNAP to a promoter is a step that can be subjected to regulation by factors (e.g. IHF) other than the sole intrinsic affinity of sigma54-RNAP for the -12/-24 site.

Bacterial Proteins↗
PubMed1999

Carrier testing program in a high-risk cystic fibrosis population from northeastern Italy. Active recruitment of relatives via probands' parents.

OBJECTIVE: To assess the practicability and monitor the results of an active carrier testing program among relatives of cystic fibrosis (CF) patients. METHODS: Parents of CF patients in the Veneto and Trentino regions of northeastern Italy were asked to help recruit relatives aged between 18 and 45 years for CF mutation testing. RESULTS: Of 409 enrolled CF parents, 59.6% agreed to send to the CF Center family composition data of relatives up to the third degree, and 28.8% recruited relatives to carrier testing, providing names and addresses of those who, being contacted, expressed a willingness to be tested. The participation of parents was higher if they were young and had a child recently diagnosed with CF. Recruiting parents indicated 333 close relatives (59%) for testing. When contacted by the CF Center, 170 of these 333 (51%) attended for testing. The percentage of close relatives who spontaneously asked for the test was 5.4% before the carrier testing program started; it rose to 25.3% following the introduction of the active strategy. CONCLUSIONS: The participation of the parents of CF patients is an important factor affecting the utilization of testing by relatives. Besides this, the influence of a favorable medical and cultural context (participation of gynecologists and family doctors in testing programs, genetic education of the general population) has to be considered.

Journal Article↗
PubMedDate not supplied

Novel 2-alkyl-1alpha,25-dihydroxy-19-norvitamin D3: efficient synthesis with Julia olefination, evaluation of biological activity and development of new analyzing system for co-activator recruitment.

New 2-alkyl-1alpha,25-dihydroxy-19-norvitamin D3 analogs were efficiently synthesized. The C2-alkyl-A-ring precursors were prepared as (3R,5R)-4-alkyl-3,5-dihydroxycyclohexanones from (-)-quinic acid based on radical allylation at the C4 position of methyl (-)-quinicate. The novel CD-ring coupling partner, with the elongated two carbon unit, was synthesized from 25-hydroxy Grundmann's ketone, and applied to modified Julia olefination to construct a diene unit between the A-ring and the CD-ring. The coupling yields, including a deprotection step, were moderate (47-62%). After the separation of the diastereomers based on C2 stereochemistry using HPLC, the structure (2alpha or 2beta) was determined by 1H NMR studies including NOE (nuclear Overhauser effect) experiments. It was also found that 1H NMR chemical shifts on the A-ring showed good correlation with DeLuca's 2-methyl- and 2-ethyl-1alpha,25-dihydroxy-19-norvitamin D3 analogs. Among the synthesized 19-norvitamin D3 analogs, 2alpha-(3-hydroxypropyl)-1alpha,25-dihydroxy-19-norvitamin D3 (8a) showed almost the same potency in binding to the bovine thymus vitamin D receptor (VDR) as the natural hormone (1), while its beta-isomer had only a 3% affinity. Both 2alpha-allyl- and 2alpha-propyl-1alpha,25-dihydroxy-19-norvitamin D3 and their 2beta-analogs possessed a weak affinity for the VDR. The strong VDR ligand 8a was ca. 36-fold more potent in induction of HL-60 cell differentiation than 1 and, interestingly, even the weaker ligand, 2beta-(3-hydroxypropyl)-1alpha,25-dihydroxy-19-norvitamin D3 (8b), showed a 6.7-fold higher potency in cell differentiation activity than that of 1. Next, a novel rapid analyzing system of ligand-induced co-factor recruitment on VDR was developed using fluorophore labelled CoA and HCHO fixing of the complex. The efficiency of recruitment of co-activators would explain the discrepancy between the biological activity and the VDR affinity of the ligand.

Alkylation↗
PubMed2004

[Different enzymatic activities recruitment by specific domains of TIF2 are involved in NF-kappaB transactivation].

We have previously shown that nuclear receptor coactivator overexpression significantly enhanced NF-kappaB activity in a dose response manner. We studied the mechanism by which TIF2 regulates NF-kappaB activity. We determined that: 1) the p38 specific inhibitor reduces 50% NF-kappaB transcriptional activity, even in cells that overexpress distinct TIF2 deletions; 2) there is a physical interaction between TIF2 and p38 and RelA determined through in vitro translated protein binding assays; 3) TIF2 is a p38 substrate; 4) there is a physical interaction between TIF2 and IKK in TNF-alpha 20 ng/ml stimulated or not HEK 293 cell protein extract, and IkappaB only in basal conditions, determined by binding pull down assays. This NF-kappaB complex regulates its activity and targets gene expression in a determined physiologic context depending on the coactivator complex content.

Cell Nucleus↗
PubMed2002

APCs in the liver and spleen recruit activated allogeneic CD8+ T cells to elicit hepatic graft-versus-host disease.

Host APCs are required for initiating T cell-dependent acute graft-vs-host disease (GVHD), but the role of APCs in the effector phase of acute GVHD is not known. To measure the effect of tissue-resident APCs on the local development of acute GVHD, we selectively depleted host macrophages and DCs from the livers and spleens, but not from the skin, peripheral lymph nodes (PLN), or mesenteric lymph nodes (MLN), of C57BL/6 (B6) mice by i.v. administration of liposomal clodronate before allogeneic bone marrow transplantation. Depletion of host hepatic and splenic macrophages and DCs significantly inhibited the proliferation of donor C3H.SW CD8(+) T cells in the spleen, but not in the PLN or MLN, of B6 mice. Such organ-selective depletion of host tissue APCs also markedly reduced the trafficking of allogeneic CD8(+) T cells into the livers and spleens, but not PLN and MLN, of B6 recipients compared with that of the control mice. Acute hepatic, but not cutaneous, GVHD was inhibited as well, resulting in improved survival of liposomal clodronate-treated B6 recipients. When C3H.SW CD8(+) T cells were activated in normal B6 recipients, recovered, and adoptively transferred into secondary B6 recipients, activated donor CD8(+) T cells rapidly migrated into the livers and spleens of control B6 recipients but were markedly decreased in B6 mice that were depleted of hepatic and splenic macrophages and DCs. Thus, tissue-resident APCs control the local recruitment of allo-reactive donor T cells and the subsequent development of acute GVHD.

Acute Disease↗
PubMed2001

The Swi5 activator recruits the Mediator complex to the HO promoter without RNA polymerase II.

Regulation of HO gene expression in the yeast Saccharomyces cerevisiae is intricately orchestrated by an assortment of gene-specific DNA-binding and non-DNA binding regulators. Binding of the early G1 transcription factor Swi5 to the distal URS1 element of the HO promoter initiates a cascade of events through recruitment of the Swi/Snf and SAGA complexes. In late G1, binding of transcription factor SBF to promoter proximal sequences results in the timely expression of HO. In this work we describe an important additional layer of complexity to the current model by identifying a connection between Swi5 and the Mediator/RNA polymerase II holoenzyme complex. We show that Swi5 recruits Mediator to HO by specific interaction with the Gal11 module of the Mediator complex. Importantly, binding of both the Gal11 and Srb4 mediator components to the upstream region of HO is independent of the SBF factor. Swi/Snf is required for Mediator binding, and genetic suppression experiments suggest that Swi/Snf and Mediator act in the same genetic pathway of HO activation. Experiments examining the kinetics of binding show that Mediator binds to HO promoter elements 1.5 kb upstream of the transcription start site in early G1, but this binding occurs without RNA Pol II. RNA Pol II does not bind to HO until late G1, when HO is actively transcribed, and binding occurs exclusively to the TATA region.

Cell Cycle Proteins↗
PubMed2003

Active recruitment of DNA methyltransferases regulates interleukin 4 in thymocytes and T cells.

How T cells regulate interleukin 4 (IL-4) expression is not completely understood. We show here that single-positive thymocytes express IL-4, but attenuate GATA-3 expression, recruit DNA methyltransferases (Dnmts) to the Il4-Il13 locus and downregulate IL-4 expression as they mature into T cells. Type 2 polarization blocks Dnmt1 recruitment, enhances histone H3 Lys4 methylation (indicative of accessible chromatin) and initiates DNA demethylation of the locus. Dnmt1-/- CD4 and CD8 T cells derepress IL-4 expression considerably, demethylate DNA and increase H3 Lys4 methylation without affecting GATA-3 expression, demonstrating that Dnmt1 and DNA methylation are essential for proper Il4 regulation. These results indicate that Dnmts, DNA and histone methylation, and transcription factors 'collaborate' to determine appropriate Il4 expression patterns.

Animals↗
PubMed1997

Recruitment, activation and proliferation of CD8+ memory T cells in an immunoprivileged site.

The capacity of a memory cytotoxic T lymphocyte (CTL) population to protect against viral infections is well established, but the processes underlying this protection are less well understood. We have used heterotypic intranasal immunization with influenza A/X31 (H3N2) to protect against a subsequent infection with the neurovirulent influenza A/WSN (H1N1) in either the cerebrospinal fluid or the immunoprivileged brain parenchyma. Viral clearance from both sites was associated with a local infiltration and proliferation of A/WSN-specific CD8+ T cells. Infection in the cerebrospinal fluid elicited a proliferative response in the draining lymph nodes, an anti-H1N1 serum antibody response and an increase in the extracerebral A/WSN-specific CTL precursor frequency. In contrast, infection in the brain parenchyma elicited no lymph node proliferative response or serum antibody response and caused a transient decrease in the extracerebral CTL precursor frequency. Thus the memory CTL population protected against an intracerebral viral infection independent of any immune response occurring in systemic lymphoid tissue.

Animals↗
PubMed1993

Effect of catalytically active recruited crystallins on lens metabolism.

The impact on duck lens metabolism of recruited epsilon-crystallin/LDH-B4 and tau-crystallin/enolase was investigated by NMR spectroscopy. A comparison of the duck lens metabolite profile with that of the calf in which recruited crystallins are absent revealed significant increases in ATP, alpha-glycerophosphate (alpha-GP) and pyridine dinucleotide concentrations. The alterations in the concentrations of ATP and alpha-GP appear to be related to both the high concentration of NAD and the elevated reduced to oxidized NADH/NAD+ ratio.

Adenosine Triphosphate↗
PubMed1983

An analysis of health physics employee recruitment activity: 1977-82.

Monthly listings of the Health Physics Society Placement Center from 8/77 to 6/82 were tabulated and analyzed for the temporal and regional trends in various areas of health physics. Almost half of listing employers advertised only a single position in 5 yr. Civilian nuclear power and its associated industrial support accounted for approximately half of the total positions available. Total annual employer and position listings increased sharply several months after the Three Mile Island incident. Activity has remained elevated since that time, and appears to have reached a plateau within the past year. A wide variety of professional positions were advertised in each region of the U.S. Recent data on numbers of graduating health physicists, plus a reasonable estimate of the number of new positions made available in recent years, imply current regional shortages of adequately trained personnel, particularly in the Far West, Rocky Mountain and South Central regions, but possibly also nationwide.

Health Physics↗
PubMedDate not supplied

Drug development, clinical trials, cultural heterogeneity in Alzheimer disease: the need for pro-active recruitment.

This article discusses the development of drugs and treatments in the context of issues of genetics, ethnicity, and culture. A brief overview of drug development, clinical trials methods, advertising and marketing practices, and the Alzheimer's Disease Cooperative Study (ADCS) recruitment program is followed by recommendations for enhancing diversity in the development of drugs for Alzheimer's disease.

Alzheimer Disease↗