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PubMed2005

[LAP proteins: new gatekeepers of epithelial homeostasis].

Cell proliferation and cell differentiation are balanced processes required for the correct development and maintenance of tissues, including epithelial tissues. Disruption of this balance by downregulation or loss of function of gatekeepers of epithelial homeostasis may unleash tumor suppressing activities leading ultimately to tumorigenesis. Among the newcoming actors involved in epithelial cell polarity, recent data shed light on the crucial role played by the LAP (LRR And PDZ) protein family. LAP proteins assemble receptors, cytoplasmic adaptors and enzymes in multimolecular networks important for the different steps of epithelial differentiation : adhesion, building of tight junctions and trafficking of proteins along the secretory pathway. Furthermore, genetic studies in invertebrates and vertebrates have installed LAP proteins not only as crucial determinants for epithelial integrity but also as key regulators of cell proliferation and embryonic development.

Animals↗
PubMed2003

Early growth response 1 protein, an upstream gatekeeper of the p53 tumor suppressor, controls replicative senescence.

The proliferation of most primary cells in culture is limited by replicative senescence and crisis, p53-dependent events. However, the regulation of p53 itself has not been defined. We find that deletion of the early growth response 1 (EGR1) transcription factor leads to a striking phenotype, including complete bypass of senescence and apparent immortal growth consistent with loss of a suppressor gene. EGR1-null mouse embryo fibroblasts (MEFs) exhibit decreased expression of p53, p21(Cip1/Waf1), and other p53 "marker" proteins. Precrisis WT but not EGR1-null cells exhibit irradiation-induced arrest. WT MEFs that emerge from crisis exhibit a mutated p53 (sequence confirmed), colony formation, and tumorigenicity. In contrast, high-passage EGR1-null MEFs retain the WT p53 sequence but with much reduced expression, remain untransformed, and grow continuously. An EGR1-expressing retrovirus restores p53 expression and sencescence to EGR1-null but not p53-null MEFs or postcrisis WT cells. Taken together, the results establish EGR1 as a major regulator of cell senescence and previously undescribed upstream "gatekeeper" of the p53 tumor suppressor pathway.

Animals↗
PubMed2003

Sur domains that associate with and gate KATP pores define a novel gatekeeper.

Structure-function analyses of K+ channels identify a common pore architecture whose gating depends on diverse signal sensing elements. The "gatekeepers" of the long, ATP-inhibited KIR6.0 pores of KATP channels are ABC proteins, SURs, receptors for channel opening and closing drugs. Several competing models for SUR/KIR coupling exist. We show that SUR TMD0, the N-terminal bundle of five transmembrane helices, specifically associates with KIR6.2, forcing nearly silent pores to burst like native KATP channels and enhancing surface expression. Inclusion of adjacent submembrane residues of L0, the linker between TMD0 and the stimulatory nucleotide- and drug-binding ABC core, generates constitutively active channels, whereas additional cytoplasmic residues counterbalance this activation establishing a relationship between the mean open and burst times of intact pores. SUR fragments, lacking TMD0, fail to modulate KIR. TMD0 is thus the domain that anchors SUR to the KIR pore. Consistent with data on chimeric ABCC/KIRs and a modeled channel structure, we propose that interactions of TMD0-L0 with the outer helix and N terminus of KIR bidirectionally modulate gating. The results explain and predict pathologies associated with alteration of the 5' ends of clustered ABCC8 (9)/KCNJ11 (8) genes.

ATP-Binding Cassette Transporters↗
PubMed2005

Bacteriophage T4 helicase loader protein gp59 functions as gatekeeper in origin-dependent replication in vivo.

Bacteriophage T4 initiates origin-dependent replication via an R-loop mechanism in vivo. During in vitro reactions, the phage-encoded gp59 stimulates loading of the replicative helicase, gp41, onto branched intermediates, including origin R-loops. However, although gp59 is essential for recombination-dependent replication from D-loops, it does not appear to be required for origin-dependent replication in vivo. In this study, we have analyzed the origin-replicative intermediates formed during infections that are deficient in gp59 and other phage replication proteins. During infections lacking gp59, the initial replication forks from two different T4 origins actively replicated both leading- and lagging-strands. However, the retrograde replication forks from both origins were abnormal in the gp59-deficient infections. The lagging-strand from the initial fork was elongated as a new leading-strand in the retrograde direction without lagging-strand synthesis, whereas in the wild-type, leading- and lagging-strand synthesis appeared to be coupled. These results imply that gp59 inhibits the polymerase holoenzyme in vivo until the helicase-primase (gp41-gp61) complex is loaded, and we thereby refer to gp59 as a gatekeeper. We also found that all origin-replicative intermediates were absent in infections deficient in the helicase gp41 or the single-strand-binding protein gp32, regardless of whether gp59 was present or absent. These results argue that replication from the origin in vivo is dependent on both the helicase and single-strand-binding protein and demonstrate that the strong replication defect of gene 41 and 32 single mutants is not caused by gp59 inhibition of the polymerase.

Bacteriophage T4↗
PubMed1998

Physicians as gatekeepers: will they contribute to restrict disability benefits?

OBJECTIVE: To study how general practitioners (GPs), specialists, and National Insurance Administration (NIA) medical consultants reacted to the narrowed eligibility criteria for disability benefits in Norway from 1991. DESIGN: Records of first-time applicants for disability benefits from the first quarters of 1990 and 1993 were analysed for proposals from the physicians in relation to the decision. SETTING: Two Norwegian counties, Ostfold and Møre and Romsdal. SUBJECTS: 668 applicants--half the granted cases, and all the refused ones. RESULTS: The number of applicants fell by 39% from 1990 to 1993 and the refusal frequency increased from 8 to 21%. Nevertheless, GPs recommended refusal to about the same extent as before, 8-9% of all cases, with probably a minor fall from 52 to 42% of the refused ones (p = 0.19). Specialists did not recommend more refusals than the GPs. Cases evaluated by the NIA medical consultants increased from 29 to 41%, and their concordance with the patients' GPs seemed to be approximately 50%. GPs did not give more detailed medical descriptions in 1993 than in 1990, and discussed eligibility criteria but slightly more comprehensively. CONCLUSION: GPs are willing to act as gatekeepers for social insurance benefits for their patients, also when eligibility criteria become restricted.

Adolescent↗
PubMed2003

Which enrollees bypass their gatekeepers in a point-of-service plan?

BACKGROUND AND OBJECTIVES: Like Health Maintenance Organizations, point-of-service (POS) health plans use primary care gatekeepers, and they permit self-referral to specialists at increased costs to the enrollee. The main objective of this study was to contrast patients who self-referred with those referred by their primary care physician. RESEARCH DESIGN: We conducted a cross-sectional telephone survey of 606 recent users of specialists in a large Midwestern POS health plan; response rate was 65%. We compared 148 enrollees who self-referred with 458 who had a physician referral. RESULTS: Self-referral was most common among those with a long-term relationship with a specialist (odds ratio [OR] = 2.08) and those dissatisfied with their primary care physician (OR = 3.65), and was rare among those with a long-standing relationship with a primary care physician (OR = 0.46). Most self-referred enrollees (68%) thought paying the additional cost for self-referral was worthwhile, and they were more dissatisfied with the quality and variety of the plan's specialist network. CONCLUSIONS: Continuity with a single physician influences how patients access specialty care. Expanding the panel of specialists in-network and encouraging long-term relationships with primary care physicians are likely to limit self-referral in a POS plan.

Adult↗
PubMed1996

Complementation of deletion mutations in a cloned functional cluster of Erwinia chrysanthemi out genes with Erwinia carotovora out homologues reveals OutC and OutD as candidate gatekeepers of species-specific secretion of proteins via the type II pathway.

The type II or Sec-dependent secretion system is used by diverse Gram-negative bacteria for secretion of extracellular proteins. Of the 12-15 proteins involved in secretion, the requirement for many has not been demonstrated and little is known about their functions in the secretion process. The plant pathogens Erwinia chrysanthemi and Erwinia carotovora secrete extra-cellular pectate lyases (Pels) using the type II or Out pathway. However, these two bacteria cannot secrete Pels encoded by heterologously expressed genes from the other species, suggesting the presence of species-specific recognition factors in the Out systems of the two Erwinia species. We previously reported the isolation of a cosmid clone, pCPP2OO6, from E. chrysanthemi EC16, which enables Escherichia coil to secrete heterologously expressed E. chrysanthemi Pels. Sequencing in a region required for secretion revealed the presence of 12 genes, outC-M and outO. We report here the construction of functionally non-polar mutations in each gene in the outC-M operon and outS and outB using a polA(ts) strain of E. coli to facilitate homologous recombination between out genes carrying deletions and their wild-type copies on pCPP2006. By testing for complementation of each deletion with wild-type out genes from E. chrysanthemi EC16 and E. carotovora SCRI193 we have demonstrated that: (i) each out gene is required for secretion of E. chrysanthemi PelE from E. coli with the exception of outH; (ii) each mutation can be complemented by its homologue from E. carotovora, except for outC and outD; (iii) outC and outD from E. carotovora do not confer secretion of Pel1 on the E. chrysanthemi Out system; and (iv) Pel1 secretion can be conferred on the E. chrysanthemi Out system by the presence of outC-M, S and B from E. carotovora. The data suggest that OutC and OutD are gatekeepers of the Out system involved in recognition of Pels targeted for secretion but that OutC and OutD from E. carotovora cannot be successfully assembled into the E. chrysanthemi Out system.

Bacterial Proteins↗
PubMed1998

Gatekeepers: a missed opportunity for safe transport.

OBJECTIVE: To assess whether contact with a health care provider or gatekeeper increases the use of an ambulance for patients with acute chest pain. METHODS: A convenience sample of adults > or =40 years of age presenting with a chief complaint of chest pain were interviewed by trained personnel regarding transport used to come to the ED. The study was performed at the ED of an urban university hospital. Patients with hemodynamic instability and those receiving thrombolytics or emergency angioplasty were excluded. Patients were asked about access to a primary health care provider and contact with a provider regarding this ED visit, including instructions given for transportation. RESULTS: Of the 450 interviewed patients, 42% arrived by ambulance. Those who had contact with a health care provider prior to the ED visit were less likely to come by ambulance than those without contact, 31% vs 51% (p < 0.001). Of the patients who had cardiac enzymes obtained to work up for their chest pain, 34% with health provider contact vs 57% without health provider contact arrived by ambulance (p < 0.001). Of those with acute myocardial infarction, 30% with health provider contact vs 66% without health provider contact came by ambulance (p < 0.03). Patients who recalled transport instructions from their providers tended to follow those instructions. The majority of patients who recalled no specific transport instructions arrived by personal automobile. CONCLUSION: Of patients presenting to an ED for evaluation of chest pain, those who made contact with a health care provider were less likely to arrive via ambulance.

Adult↗
PubMed2003

Protein phosphatase 2A dephosphorylation of phosphoserine 112 plays the gatekeeper role for BAD-mediated apoptosis.

BAD, a proapoptotic molecule of the BCL2 family, is regulated by reversible phosphorylation. During survival, BAD is sequestered by 14-3-3 through serine 136 phosphorylation and is dissociated from BCL-X(L) through serine 155 phosphorylation. We report that phosphoserine 112 (pSer112) dephosphorylation functions as a gatekeeper for BAD-mediated apoptosis. During apoptosis, dephosphorylation of pSer112 preceded pSer136 dephosphorylation. Dephosphorylation of pSer112 accelerated dephosphorylation of pSer136, and inhibition of pSer112 dephosphorylation prevented pSer136 dephosphorylation, indicating that dephosphorylation of pSer112 is required for dephosphorylation of pSer136. Protein phosphatase 2A (PP2A) is the major pSer112 phosphatase. PP2A competed with 14-3-3 for BAD binding, and survival factor withdrawal enhanced PP2A association with BAD. Dephosphorylation of the critical residue, pSer136, could only be blocked by inhibition of all known subfamilies of serine/threonine phosphatases, suggesting that multiple phosphatases are involved in pSer136 dephosphorylation. Inhibition of PP2A rescued FL5.12 cells from apoptosis, demonstrating a physiologic role for PP2A-mediated pSer112 dephosphorylation. Thus, PP2A dephosphorylation of pSer112 is the key initiating event regulating the activation of BAD during interleukin-3 withdrawal-induced apoptosis.

14-3-3 Proteins↗
PubMed2003

ABC of oral bioavailability: transporters as gatekeepers in the gut.

MDR1 (ABCB1), MRP2 (ABCC2), and BCRP (ABCG2) are members of the family of ATP binding cassette (ABC) transporters. These are plasma membrane transporters that are expressed in various organs. The role of MDR1 and MRP2 in the hepatobiliary system is well defined; both contribute to bile formation by transport of drugs, toxins, and waste products across the canalicular membrane. As they transport exogenous and endogenous substances, they reduce the body load of potentially harmful compounds. The role of ABCG2, which is also expressed in the canalicular membrane of hepatocytes, has not yet been fully characterised. All three proteins are also expressed in the apical membrane of enterocytes where they probably control oral availability of many substances. This important "gatekeeper" function of ABC transporters has been recognised recently and is currently under further investigation. Expression and activity of these transporters in the gut may differ between individuals, due to genetic polymorphisms or pathological conditions. This will lead to individual differences in bioavailability of different drugs, toxins, and (food derived) carcinogens. Recent information on substrates, transport mechanisms, function, and regulation of expression of MDR1, MRP2, and BCRP in different species is summarised in this review.

ATP-Binding Cassette Transporters↗
PubMed1998

Health care expenditures after introduction of a gatekeeper and a global budget in a Swiss health insurance plan.

STUDY OBJECTIVES: To assess whether the introduction of "managed care" (capitated budget and utilisation control by general practitioners) in a Swiss health insurance plan caused a selective disenrolment of plan members, and whether it achieved its goal of reducing health care expenditures. DESIGN: Controlled before-after analysis of health insurance claims. SETTING: Health insurance plan of the University of Geneva, Switzerland, which introduced managed care at the end of 1992, and comparison plan, which reimbursed health care expenditures without setting a budget or controlling access. PARTICIPANTS: Analysis of self selection: university plan members who accepted (3993) or refused (659) transfer to managed care. Analysis of change in expenditures: cohorts of persons continuously enrolled in the university (1575) and comparison (3384) plans in 1992 and 1993. MAIN RESULTS: During 1992, the year before the transformation of the university plan, persons who refused managed care had generated 35% higher expenditures than those who accepted managed care (p < 0.001). Between 1992 and 1993, expenditures per member decreased by 9% in the university cohort and increased by 11% in the comparison cohort (p = 0.004). Technical procedures (laboratory tests, physical therapy, drugs) decreased most in the university plan. No impact on hospital admissions was detected. CONCLUSIONS: Introduction of gatekeeping and budget management by physicians caused a favourable self selection process for the university plan. In addition, the managed care plan achieved a substantial decrease in overall health care expenditures in its first year of operation, chiefly by reducing outlays for technical procedures.

Adult↗
PubMed2000

Plasmodesmata: gatekeepers for cell-to-cell transport of developmental signals in plants.

Cell walls separate individual plant cells. To enable essential intercellular communication, plants have evolved membrane-lined channels, termed plasmodesmata, that interconnect the cytoplasm between neighboring cells. Historically, plasmodesmata were viewed as facilitating traffic of low-molecular weight growth regulators and nutrients critical to growth. Evidence for macromolecular transport via plasmodesmata was solely based on the exploitation of plasmodesmata by plant viruses during infectious spread. Now plasmodesmata are revealed to transport endogenous proteins, including transcription factors important for development. Two general types of proteins, non-targeted and plasmodesmata-targeted, traffic plasmodesmata channels. Size and subcellular location influence non-targeted protein transportability. Superimposed on cargo-specific parameters, plasmodesmata themselves fluctuate in aperture between closed, open, and dilated. Furthermore, plasmodesmata alter their transport capacity temporally during development and spatially in different regions of the plant. Plasmodesmata are exposed as major gatekeepers of signaling molecules that facilitate or regulate developmental programs, maintain physiological status, and respond to pathogens.

Biological Transport↗
PubMed2006

Patched1 functions as a gatekeeper by promoting cell cycle progression.

Mutations in the Hedgehog receptor, Patched 1 (Ptch1), have been linked to both familial and sporadic forms of basal cell carcinoma (BCC), leading to the hypothesis that loss of Ptch1 function is sufficient for tumor progression. By combining conditional knockout technology with the inducible activity of the Keratin6 promoter, we provide in vivo evidence that loss of Ptch1 function from the basal cell population of mouse skin is sufficient to induce rapid skin tumor formation, reminiscent of human BCC. Elimination of Ptch1 does not promote the nuclear translocation of beta-catenin and does not induce ectopic activation or expression of Notch pathway constituents. In the absence of Ptch1, however, a large proportion of basal cells exhibit nuclear accumulation of the cell cycle regulators cyclin D1 and B1. Collectively, our data suggest that Ptch1 likely functions as a tumor suppressor by inhibiting G1-S phase and G2-M phase cell cycle progression, and the rapid onset of tumor progression clearly indicates Ptch1 functions as a "gatekeeper." In addition, we note the high frequency and rapid onset of tumors in this mouse model makes it an ideal system for testing therapeutic strategies, such as Patched pathway inhibitors.

Animals↗
PubMed2002

Are islet cells the gatekeepers of the pancreas?

The pancreas is one of the body's most complex tissues composed of a mixture of endocrine and exocrine cell components. Although, islets comprise 1-2% of the pancreatic volume, there is some evidence that they control the function and the integrity of the pancreas and play the role of a gatekeeper. This review intends to highlight the importance of islet cells, not only for glucose metabolism, but also for their significant role in drug metabolism and diseases, especially in pancreatic cancer.

Animals↗
PubMed1995

Who decides? Patients, parents, or gatekeepers: pediatric decisions in the craniofacial setting.

Special ethical issues arise for the craniofacial team dealing with pediatric patients, which include competency, surrogacy, and the "best interests" standard. Medical decisions for children are made by surrogates, usually parents, who must use the "best interests" standard. The team's primary responsibility is to the child, not the parents. Children should participate as abilities allow, especially for elective procedures. Increasingly, cost considerations also influence medical decisions. The craniofacial team is often a de factor gatekeeper. Ethically responsible team behavior includes: weighing risks and benefits of proposed interventions; promoting discussion with families and patients to identify "best interests;" monitoring outcomes; and advocacy for craniofacial patients individually and at a policy level. Care guidelines and definitions of basic levels of care should be developed to assist teams with decision-making and advocacy efforts. Ethical analysis is part of both good patient care and good policy formation, and should be a part of regular team deliberations.

Abnormalities, Multiple↗
PubMed2006

TLRs regulate the gatekeeping functions of the intestinal follicle-associated epithelium.

Initiation of adaptive mucosal immunity occurs in organized mucosal lymphoid tissues such as Peyer's patches of the small intestine. Mucosal lymphoid follicles are covered by a specialized follicle-associated epithelium (FAE) that contains M cells, which mediate uptake and transepithelial transport of luminal Ags. FAE cells also produce chemokines that attract Ag-presenting dendritic cells (DCs). TLRs link innate and adaptive immunity, but their possible role in regulating FAE functions is unknown. We show that TLR2 is expressed in both FAE and villus epithelium, but TLR2 activation by peptidoglycan or Pam(3)Cys injected into the intestinal lumen of mice resulted in receptor redistribution in the FAE only. TLR2 activation enhanced transepithelial transport of microparticles by M cells in a dose-dependent manner. Furthermore, TLR2 activation induced the matrix metalloproteinase-dependent migration of subepithelial DCs into the FAE, but not into villus epithelium of wild-type and TLR4-deficient mice. These responses were not observed in TLR2-deficient mice. Thus, the FAE of Peyer's patches responds to TLR2 ligands in a manner that is distinct from the villus epithelium. Intraluminal LPS, a TLR4 ligand, also enhanced microparticle uptake by the FAE and induced DC migration into the FAE, suggesting that other TLRs may modulate FAE functions. We conclude that TLR-mediated signals regulate the gatekeeping functions of the FAE to promote Ag capture by DCs in organized mucosal lymphoid tissues.

Animals↗
PubMed1979

Physicians as gatekeepers: illness certification as a rationing device.

Illness or disability is often used as an eligibility criterion by public programs that distribute money, services, privileges, and exemptions. Physicians then play a central role in the allocation process. But physicians are caught between a large pool of applicants who want some benefit, on the one hand, and an organization with limited resources to distribute, on the other hand. Three conflicts are engendered in this gatekeeping role: the tension between trusting and mistrusting information provided by the patient, the tension between erring on the false positive side and the false negative side in diagnostic decision-making, and the tension between doing everything possible for each patient and allocating limited resources among several needy clients. Several non-medical factors influence the ultimate outcome of this allocation process, which, in theory, rests on clinical decision-making: the specificity and restrictiveness of the formal definitions of illness and disability used by a program; the structure of the determination process; the overall policy of the organization on distribution of benefits; and the ability of the organization to use administrative review, direct incentives, and written standards to control the certifying behavior of physicians.

Decision Making↗
PubMed1986

Diagnosing the physician as gatekeeper in hospice marketing.

The attitudes and opinions gatekeeping physicians hold toward hospice are important in critically evaluating hospice marketing efforts. Based on a national sample of physicians, this article examines their perceived role in the referral process and their evaluation of critical care components, hospice administration, and communication vehicles. Recommendations for future marketing efforts are offered.

Attitude of Health Personnel↗