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At least 307 records · Page 17Linked to original sources
PubMed1991

Mechanism of activation of A2 adenosine receptors. II. A restricted collision-coupling model of receptor-effector interaction.

Existing models describing the kinetics of receptor-effector interaction were found to be insufficient to account for the experimental findings on adenylate cyclase activation by A2 adenosine receptors described in the preceding manuscript [Mol. Pharmacol. 39: 517-523 (1991)]. We have, therefore, chosen another approach and have developed discrete computer simulations of receptor-effector interactions taking place on a spherical membrane. These simulations were based on the following principles: (a) receptors activate effectors in a catalytic manner, and (b) diffusion of receptors and effectors is slow, so that receptors will only activate effectors that are in their vicinity at the time of agonist occupation. Using several experimentally determined parameters, these simulations could reproduce the experimental findings on adenylate cyclase activation by A2 adenosine receptors described in the preceding manuscript. In addition, by appropriate choice of the simulation parameters, they are shown to accommodate the behavior of several other models of receptor-effector interactions.

Azides↗
PubMed1985

Murine interstitial nephritis. III. The selection of phenotypic (Lyt and L3T4) and idiotypic (RE-Id) T cell preferences by genes in Igh-1 and H-2K characterizes the cell-mediated potential for disease expression: susceptible mice provide a unique effector T cell repertoire in response to tubular antigen.

The effector T cell repertoire in experimental interstitial nephritis was examined in a variety of susceptible and nonsusceptible mice. We observed that L3T4+ effector T cells in disease-susceptible mice disappear soon after immunization in preference to the emergence of Lyt-2+ effector cells. These latter cells respond with delayed-type hypersensitivity to tubular antigen in the context of H-2K. Such cells also express idiotypes (RE-Id) shared with kidney-bound alpha TBM-Ab that are regulated by an interactional effect of genes in Igh-1 and H-2K. These Lyt-2+ effector cells can be removed from renal infiltrates, and the transfer of similar cells under the renal capsule of naive mice results, within 5 days, in local interstitial nephritis. Nonsusceptible mice, however, not having these immune response genes, produce either L3T4+, Lyt-1+, RE-Id- effector T cells, which only respond to tubular antigen in the context of I-A, or Lyt-2+, RE-Id- T cells, which may lack very fine specificity. These findings suggest that susceptible mice carry a unique set of immune response genes that promote a T cell selection process that operates after induction, during the differentiation and development of disease-producing effector T cells.

Animals↗
PubMed1989

Detection and characterization of anti-tumour effector cells in Meth-A-bearing mice treated with recombinant human interleukin 2.

When Meth-A fibrosarcoma-bearing BALB/c mice were injected subcutaneously with 10 micrograms of recombinant human interleukin 2(rIL-2) once a day for 10 days, tumour growth inhibition was in the range of 22-31% of that of the control animals. Anti-tumour effector cells against Meth-A were detected in the spleen cells of the tumour-bearing BALB/c mice injected with rIL-2, using a modified Winn-type neutralization assay with the auxiliary injection of rIL-2. To induce the strongest anti-tumour activity in this assay system, the following were necessary: 1) the effector cells were derived from tumour-bearing BALB/c mice; 2) the donors of the effector cells were injected with rIL-2; 3) the recipient mice in the Winn assay were auxiliarily injected with rIL-2 (a modified Winn assay). The anti-tumour effector activity detected in the modified Winn assay was inhibited by treatment with anti-CD8 or anti-asialo GM1 antibodies plus complement (C), but not completely. We supposed that at least two kinds of anti-Meth-A effector cells with different surface antigens, positive for CD8 and asialo GM1 antigens, were induced in the Meth-A-bearing BALB/c mice injected with rIL-2; these populations seemed to function independently and at least partly as anti-tumour effector cells in this tumour-host system. These spleen cells showed in vitro cytotoxicity against Meth-A cells, which are resistant to NK cells, if the activity was measured in a 24 h 51Cr-release assay in the presence of rIL-2.

Animals↗
PubMed1987

Mechanism of defective NK cell activity in patients with acquired immunodeficiency syndrome (AIDS) and AIDS-related complex. II. Normal antibody-dependent cellular cytotoxicity (ADCC) mediated by effector cells defective in natural killer (NK) cytotoxicity.

Our studies and other investigations have shown that NK effector cells can also mediate antibody-dependent cellular cytotoxicity (ADCC) through the use of the Fc gamma receptor on the NK cell membrane. Peripheral blood lymphocytes (PBL) derived from patients with acquired immunodeficiency syndrome (AIDS) and AIDS-related complex exhibit a poor NK activity due to a defective "trigger" required for activation in the lethal hit stage of the NK lytic pathway. Consequently, it was important to delineate whether the defect in AIDS NK cells affected the ADCC function. By using the 51Cr-release assay, the ADCC cytotoxic activity of AIDS PBL was found to be within the normal range, despite the absence of significant NK activity. Several experiments corroborated that the same effector cells mediate both NK CMC and ADCC. Depletion of Fc gamma R-bearing cells resulted in elimination of both the ADCC and NK cytotoxic functions. Single cell analyses, using one- and two-target cell conjugates, revealed that the frequency of ADCC effector:target conjugates and the frequency of killer cells from AIDS PBL were comparable to the frequencies seen in the normal controls. However, when mixtures of NK and ADCC targets were used to form mixed two-target conjugates, the AIDS effector cells lysed only the bound ADCC target, whereas the normal effector cells lysed both the bound NK and ADCC targets. These results demonstrate clearly that the same NK/K effector cells from AIDS PBL, defective in NK activity, are not impaired in mediating ADCC activity. These findings were supported by the demonstration that AIDS PBL stimulated with ADCC targets, but not with NK targets, released NK cytotoxic factors, postulated mediators of the NK CMC reaction. These findings indicate that the NK/K cells in AIDS are triggered normally for ADCC activity but are not triggered for NK activity. Furthermore, the results indicate that the lytic machinery is not impaired in the AIDS NK/K cells.

AIDS-Related Complex↗
PubMed1985

The reorientation of the Golgi apparatus and the microtubule-organizing center in the cytotoxic effector cell is a prerequisite in the lysis of bound target cells.

This investigation is concerned with the detailed mechanisms of cytotoxicity, and in particular, with early cell surface and intracellular events that occur upon the binding of a cytotoxic effector cell to its susceptible target. In earlier studies, we have shown by immunofluorescence microscopy that when cloned natural killer (NK) and cytolytic T lymphocyte (CTL) cells bind to susceptible target cells, a rapid and coordinate reorientation of the perinuclear Golgi apparatus and the microtubule-organizing center (MTOC) occurs inside the effector cell so that the two organelles face the bound target. It was proposed that the purpose served by this reorientation is to direct Golgi-derived secretory vesicles, containing one or more cytotoxic components, to the area of target cell binding. In order to establish more firmly that this reorientation of the two organelles is an essential early event in cytotoxicity, we have performed three different types of experiments. 1) Upon binding cloned effector cells to susceptible targets in the presence of Mg+2 but absence of Ca+2, conditions in which no killing occurs, we found that no reorientation of the MTOC in the effector cell is induced; however, the addition of CA+2 to these cell couples results in a rapid MTOC reorientation. 2) With a lysis-defective subclone derived from a cytolytic NK clone, binding to target cells did not induce an MTOC reorientation in the defective killer cell. 3) In multitarget conjugates formed with single CTL, the MTOC in the CTL was oriented to face that one target cell which was in the process of lysis at the time. These results, together with our earlier findings, strongly indicate that a Golgi/MTOC reorientation inside the target-bound effector cell is a pre-requisite for the effective lysis of the target. They also reveal the existence, previously unrecognized, of a specific signaling mechanism from the viable target cell to the effector cell, which must be involved in the triggering of this Golgi/MTOC reorientation. These conclusions are consistent with the proposal that a polar cytotoxic secretory mechanism is responsible for target cell lysis.

Animals↗
PubMed1983

Involvement of carbohydrate moieties in the expression of effector activity of cytotoxic T cells against syngeneic tumor cells.

Cytotoxic T lymphocytes (CTL) were raised against syngeneic plasmacytoma MOPC-315 cells by culturing spleen cells immunized with MOPC-315 cells 7 to 14 days previously, in the presence of MOPC-315 cells for 5 days. The cytotoxic activity of these CTL was blocked by D-mannose, indicating that mannose-containing carbohydrate moieties are involved in the expression of cytotoxic activity. Investigations were performed to determine which cells, effector or target, possess carbohydrate moieties, by employing procedures by which a part or most of the carbohydrate on cells can be removed. When target cells were treated with 2-deoxy-D-glucose, tunicamycin or trypsin, the levels of cytotoxic activity of the CTL were reduced. However, the reduced activities were still blocked by adding D-mannose at the effector phase. Treatment with alpha-mannosidase did not affect the level of cytotoxicity or mannose-sensitivity. In contrast, when effector cells were treated with tunicamycin by adding it to the culture one day before harvest, the level of cytotoxic activity was reduced, but the cytotoxic activity was no longer blocked by D-mannose. A similar result was obtained when effector cells were treated with periodate after 5 days of culture. However, the treatment of effector cells with alpha-mannosidase did not affect the cytotoxicity of the CTL. Thus, it was shown that effector cells possess mannose-containing carbohydrate moieties which are involved in the full expression of CTL to syngeneic MOPC-315 cells.

Animals↗
PubMed1984

Mechanism of cell-mediated cytotoxicity at the single cell level. VI. Direct assessment of the cytotoxic potential of human peripheral blood non-lytic effector-target cell conjugates.

Single cell cytotoxicity assays reveal that a large percentage of lymphocytes are unable to kill attached targets in a 4- to 18-hr assay. Additional signals (in the form of lectin or anti-target antibody) delivered to target-bound lymphocytes enable these previously non-lytic lymphocytes to kill attached target cells. This finding was obtained by using a modification of the single cell assay, in which lectin or target cell antibody is incorporated into agarose with preformed lymphocyte-target conjugates. Human peripheral blood lymphocytes (PBL) or Percoll density gradient-enriched large granular lymphocytes (LGL) were used as effector cells in natural killer (NK), antibody-dependent cellular cytotoxicity (LDCC) assay systems. The targets used were NK-sensitive K562 and Molt-4 and NK-insensitive Raji. Several findings were made in the modified single cell assay, namely a) the frequency of cytotoxic NK or ADCC effector cells was not augmented, suggesting that the initial trigger was sufficient for lytic expression in these instances. Furthermore, these results showed that the NK-sensitive targets used do not bind nonspecifically to the LDCC effector cells. K562 coated with Con A, however, serve as LDCC targets. b) The frequency of two target conjugate lysis by NK/K effectors was not augmented by Con A. These results suggest that Con A does not potentiate the killing of multiple targets bound to a single cytotoxic lymphocyte. c) Although conjugates formed between LGL or PBL and NK-insensitive Raji are non-lethal, significant lysis was observed when these conjugates were suspended in Con A or antibody agarose. These results demonstrate that Raji bind to cytotoxic NK, K, and LDCC effector cells, but are lysed only when the appropriate trigger is provided. d) The cytotoxic potential of non-lytic conjugates appears to lie within the low density Percoll fraction, although the high density lymphocytes are able to nonlethally bind to targets. Altogether the results demonstrate that target recognition and/or binding by the effector cells is a distinct event from the trigger or lytic process. The implications of these findings are discussed.

Animals↗
PubMed1995

Regulation by corticosteroids of Th1 and Th2 cytokine production in human CD4+ effector T cells generated from CD45RO- and CD45RO+ subsets.

Corticosteroids (CS) are widely used as immunosuppressive and anti-inflammatory agents, but their mechanism of action is not well understood. In this study we analyzed the effects of CS on the growth and differentiation of human CD4+45RO- "naive" and CD4+45RO+ "memory" T cells. To generate effector T cells secreting large amounts of Th1 and Th2 cytokines, FACS-sorted naive and memory subsets were primed and restimulated in vitro via the TCR in the presence of IL-2. CS added during priming reduced clonal expansion of both T cell populations, but the memory subset was 100-fold less sensitive. At lower concentrations, CS favored the development of effector T cells (from both subsets), which upon restimulation produced large amounts of the anti-inflammatory cytokine IL-10, but low amounts of IL-4, IL-5, or IFN-gamma. Interestingly, CS displayed different effects if it was added only during the restimulation of effector T cells. CS were unable to suppress clonal expansion of restimulated effector T cells. In effector T cells derived from the naive subset, CS induced production of IL-4 and IL-10, but blocked production of IL-5 and IFN-gamma. In effector T cells generated from the memory subset, CS blocked production of IL-4, IL-5, and IL-10, but inhibited production of IFN-gamma by only 50%, even if 100-fold higher concentrations of CS were applied. These results indicate that persistent TCR stimulation, e.g., in chronic infection, may reduce the sensitivity of T cells to the antiproliferative effects of CS. Furthermore, the potential of CS to increase or suppress IL-4 and IL-10 production depending on the stage of T cell activation may explain in part the beneficial effects of CS in the treatment of acute inflammation and chronic allergic/asthmatic diseases.

Adrenal Cortex Hormones↗
PubMed1994

Rab3A effector domain peptides induce insulin exocytosis via a specific interaction with a cytosolic protein doublet.

A key protein involved in the regulated exocytotic mechanism in neuroendocrine cells is the GTP-binding protein, Rab3A. Rab3A is thought to mediate exocytosis by an interaction of its effector domain with a putative effector protein. We demonstrate here that Rab3A effector domain peptides specifically stimulated insulin exocytosis in electroporated insulin-secreting cells (K0.5 activation, 6-8 microM) in a Ca(2+)-independent manner, although in the presence of Ca2+ insulin exocytosis was further potentiated. By using a 125I-radiolabeled photoactivated cross-linking Rab3A effector domain peptide, we identified a cytosolic protein doublet (REEP-1 and REEP-2), which specifically interacted with the Rab3A effector domain. Competitive inhibition studies revealed this protein-protein interaction to be at a concentration equivalent to that required for Rab3A effector domain peptides to trigger insulin exocytosis (Ki, 6-8 microM). Furthermore, under basal secretory conditions REEP-1 and -2 were membrane-associated, but upon stimulation of exocytosis they were released into a cytosolic fraction. Our results suggest that REEP-1 and -2 are part of the regulated exocytotic machinery, and their dissociation upon stimulation of hormone release (likely from a protein complex) may be essential to the mechanism that triggers regulated exocytosis in pancreatic beta-cells.

Amino Acid Sequence↗
PubMed1976

Secondary cytotoxic cell response to lymphocytic choriomeningitis virus. I. Kinetics of induction in vitro and yields of effector cells.

Secondary (memory) cell-mediated cytotoxic responses in lymphoid cells from CBA/H mice pre-primed with lymphocytic choriomeningitis virus (LCM) 5-7 weeks previously were induced by culturing these cells in vitro with syngeneic, infected peritoneal cells at 37 degrees for periods of up to 5 days. Cytotoxic effectors were assayed against LCM infected, H-2 compatible target cells in a 51Cr release assay. Response was greater with a higher ratio (1:10) of infected peritoneal cells:pre-primed cells than with lower ratios (e.g. 1:250). Separating responders from infected cells by a 450 mmum nucleopore membrane (coarse enough to allow passage of virus particles) still permitted induction of a secondary response whilst interposition of a 50 mmum nucleopore membrane (which apparently prevented transit of virus particles) virtually abolished the secondary response. Removal of phagocytic cells from responders prior to setting up memory cultures greatly reduced responders' capacity to be induced. Fixed, infected stimulators still induced strong secondary responses. Secondary response was maximal with spleen cells, peripheral blood lymphocytes, or pooled iliac and lumbar lymph node cells. Thymocytes responded less well, whilst mesenteric lymphoid cells and peritoneal cells gave minimal responses. Effector cells from memory cultures killed targets with single-hit kinetics and a rectilinear log effectors: log targets lysed relation held. Memory spleen cells developed increasing cytolytic activity from 2 to 5 days in culture. Memory-generated effectors were markedly potent by day 5, e.g. giving 70 per cent specific release at a killer:target ratio of 0-8:1. Peak DNA synthesis occurred on day 4. We conclude that memory effectors as a population differ in kinetics and potency from effectors obtained by primary viral challenge in the mouse.

Animals↗
PubMed1999

Immunotherapy with effector cells and IL-2 of lymph node metastases of human squamous-cell carcinoma of the head and neck established in nude mice.

We have previously reported that immune anti-tumor effector cells, both cytotoxic T lymphocytes (CTLs) and IL-2-activated natural killer (A-NK) cells, are effective at eliminating human head-and-neck cancer (HNC) targets in vitro and in vivo in xenograft models. In this study, these 2 types of human effector cell were compared for the ability to prevent the development of lymph node metastases in a metastasis model of human squamous-cell carcinoma of the head and neck (SCCHN) established in nude mice. A tumor cell line, OSC-19, was injected into the floor of the mouth in nude mice, and the tumor grew progressively and metastasized to cervical lymph nodes by day 21. As effector cells, a human HLA-A2-restricted CTL line recognizing a shared antigen on OSC-19 and human non-MHC-restricted A-NK cells were used. Both types of effector cell mediated high levels of lysis against OSC-19 targets in 4-hr (51)Cr-release assays. Administration of human CTLs or A-NK cells and IL-2 to the site of tumor growth in mice with 7-day OSC-19 tumors resulted in significant reduction of the number of lymph node metastases relative to untreated or sham-operated controls or to mice treated with IL-2 without the effector cells. Our results suggest that in a xenograft model of human SCCHN implanted in the oral cavity of nude mice, the development of lymph node metastases can be successfully controlled by adoptive transfer of human SCCHN-specific CTLs or SCCHN-reactive A-NK cells plus IL-2.

Animals↗
PubMed1980

Antibody-dependent, cell-mediated cytotoxicity against human red blood cells: correlation of effector cell type with enzymatic alteration of the target cell surface.

Target cell factors, which contribute to the determination of the effector cell type in an antibody-dependent, cell-mediated cytotoxicity system were studied. Human red blood cells (RBC) were treated with papain and investigated by transmission and scanning electron microscopy (TEM and SEM). Both untreated (native) and treated 0 Rh+ RBC were labeled with 51Cr, sensitized with anti-D immunoglobulin and incubated with unfractionated autologous peripheral blood mononuclear cells. With native RBC, immune lysis was proportional to the number of phagocytes: enrichment of effectors in phagocytes increased lysis, while depletion of phagocytes from effectors decreased lysis. Following papain treatment of target RBC, lysis by unfractionated mononuclear effectors was markedly augmented; since this effect was not diminished by decrease of phagocytes to less than 2%, the augmented lysis was not due to the number of phagocytic effectors. TEM and SEM of enzyme-treated RBC showed spherocytosis with varying degrees of crenation and blurring and irregularities of the cellular membranes. The results suggest that papain-induced alterations in the target RBC rendered them susceptible to lysis by interaction between anti-D antibody and peripheral blood lymphocytes.

Antibody-Dependent Cell Cytotoxicity↗
PubMed1981

Cytotoxic T cell recognition of Epstein-Barr virus-infected B cells. I. Specificity and HLA restriction of effector cells reactivated in vitro.

The experiments show that the phenomenon of regression, seen exclusively in Epstein-Barr (EB) virus-infected cultures of mononuclear cells from EB virus antibody-positive donors, is mediated by cytotoxic T cells reactivated in vitro and specifically recognizing an EB virus-induced lymphocyte-detected membrane antigen LYDMA. Thus, effector T cells from regressing cultures kill autologous EB virus-transformed cells but not autologous pokeweed mitogen-stimulates lymphoblasts nor any of a range of EB virus genome-negative human hemopoietic cell lines (K562, HSB2, BJAB, EB4) particularly sensitive to nonspecific natural killer-like activities. Moreover, these reactivated effector cells exhibit classical HLA restriction of target cell recognition; in a survey of 14 effector cell donors, preferential lysis of the autologous virus-transformed line was a consistent feature, while the relative degree of lysis of allogeneic lines was in general directly related to the number of HLA-A and B antigens shared between effector and target cells. The pattern of reactivity shown by effector T cell preparations from any one donor was strikingly reproducible, and the results from a number of donors revealed differences between particular HLA-A and B antigens with respect to the level of EB virus-specific killing which was associated with sharing through these determinants.

B-Lymphocytes↗
PubMed1992

CD4+ suppressor cells of autoimmune encephalomyelitis respond to T cell receptor-associated determinants on effector cells by interleukin-4 secretion.

We have previously demonstrated that CD4+ suppressor T cells (Ts) inhibit the secretion of interferon (IFN)-gamma, but not interleukin (IL)-2, by effector cells of experimental autoimmune encephalomyelitis (EAE). Moreover, CD4+ Ts appear to regulate IFN-gamma by secretion of transforming growth factor-beta. We now show that CD4+ Ts produce a lymphokine with IL-4 activity in response to a determinant associated with EAE effector cells. CD4+ Ts do not proliferate or secrete IFN-gamma, IL-2, or IL-4 in response to myelin basic protein, nor do CD4+ Ts proliferate or secrete IL-2 when co-cultured with irradiated EAE effector cells. Rather, CD4+ Ts secrete IL-4 when co-cultured with either irradiated effector spleen cells or irradiated encephalitogenic line cells. CD4+ Ts do not secrete IL-4 in response to OVA-primed spleen cells, suggesting that the suppressor cells recognize a determinant specific to encephalitogenic T cells. Furthermore, CD4+ Ts secrete IL-4 when cultured with synthetic T cell receptor (TcR) V beta 8, but not TcR V beta 14 peptide, in the presence of antigen-presenting cells. This response is major histocompatibility complex class II restricted as demonstrated by inhibition of the response with anti-class II monoclonal antibody. These results suggest that CD4+ Ts recognize a determinant associated with TcR on the surface of EAE effector cells and respond by secreting IL-4, in a manner analogous to the Th2 lymphocyte subtype.

Amino Acid Sequence↗
PubMed1977

ADCC effector cells in a murine adenocarcinoma. I. Evidence for blood-borne bone-marrow-derived monocytes.

The origin and identity of effector cells for anti-body-dependent cell-mediated cytotoxicity and/or growth inhibition (ADCC) found in the murine mammary adenocarcinoma T1699 were investigated. Non-phagocytic, non-adherent ADCC effector cells were identified in bone marrow, peripheral blood and the host fraction of the tumor but not from lymphoid organs. These cells were shown to be distinct from the specific growth-inhibitory "armed monocytes" also identified in situ. The ADCC effector cells possess low levels of EA Fc receptors and appear to express a macrophage-associated antigen. Both the bone-marrow and the in situ effector cells became phagocytic after overnight incubation, providing further evidence for the monocyte-macrophage lineage of these cells. The results suggest that bone-marrow-derived blood-borne monocytes are the principal ADCC effector cells localizing in the mammary adenocarcinoma T1699. The parallels between tumor-induced immunity and cellular resistance to infectious agents involving hypersensitivity reactions and blood-borne monocytes are discussed.

Adenocarcinoma↗
PubMed1978

Studies of effector cell, antibody, and target cell interactions in natural cell-mediated cytotoxicity.

IgG antibodies bound to effector cells through Fc receptors were observed to determine the specificity of natural cell-mediated cytotoxicity (NCMC) against cultured target cells. When effector lymphocytes were isolated from the peripheral blood of most individuals, they already possessed natural antibodies specific for antigens on cultured cells. Since they lacked IgG antibodies specific for antigens on sheep red blood cell (SRBC) targets, natural cytotoxicity against SRBC was almost non-existent. Effector cells incubated in IgG anti-SRBC became specifically cytotoxic to SRBC. In the process, NCMC and antibody-dependent cell-mediated cytotoxicity was diminished, indicating that arming with anti-SRBC replaced natural antibodies and occupied Fc receptors on effector cells. Thus, treating effector cells with serum may result in increased or decreased cytotoxicity depending upon the specificity of antibodies within the serum. This type of modulation of NCMC occurs at the interaction between antibody Fc and Fc receptors and can explain blocking and unblocking.

Animals↗
PubMed1995

Rac GTPase interacts with GAPs and target proteins through multiple effector sites.

Rac, a small GTPase in the ras superfamily, regulates at least two biological processes in animal cells: (i) the polymerization of actin and the assembly of integrin complexes to produce lamellipodia and ruffles; and (ii) the activity of an NADPH oxidase in phagocytic cells. NADPH oxidase activation is mediated through a rac effector protein, p67phox, and using chimeras made between rac and the closely related GTPase, rho, we have identified two distinct effector sites in rac, one N-terminal and one C-terminal, both of which are required for activation of p67phox. The same two effector sites are essential for rac-induced actin polymerization in fibroblasts. p65PAK, a ubiquitous serine/threonine kinase, interacts with rac at both the N- and C-terminal effector sites, but the GTPase-activating protein, bcr interacts with rac at a different region. This makes p65PAK, but not bcr, a candidate effector of rac-induced lamellipodium formation.

3T3 Cells↗
PubMed2003

HES and HERP families: multiple effectors of the Notch signaling pathway.

Notch signaling dictates cell fate and critically influences cell proliferation, differentiation, and apoptosis in metazoans. Multiple factors at each step-ligands, receptors, signal transducers and effectors-play critical roles in executing the pleiotropic effects of Notch signaling. Ligand-binding results in proteolytic cleavage of Notch receptors to release the signal-transducing Notch intracellular domain (NICD). NICD migrates into the nucleus and associates with the nuclear proteins of the RBP-Jkappa family (also known as CSL or CBF1/Su(H)/Lag-1). RBP-Jkappa, when complexed with NICD, acts as a transcriptional activator, and the RBP-Jkappa-NICD complex activates expression of primary target genes of Notch signaling such as the HES and enhancer of split [E(spl)] families. HES/E(spl) is a basic helix-loop-helix (bHLH) type of transcriptional repressor, and suppresses expression of downstream target genes such as tissue-specific transcriptional activators. Thus, HES/E(spl) directly affects cell fate decisions as a primary Notch effector. HES/E(spl) had been the only known effector of Notch signaling until a recent discovery of a related but distinct bHLH protein family, termed HERP (HES-related repressor protein, also called Hey/Hesr/HRT/CHF/gridlock). In this review, we summarize the recent data supporting the idea of HERP being a new Notch effector, and provide an overview of the similarities and differences between HES and HERP in their biochemical properties as well as their tissue distribution. One key observation derived from identification of HERP is that HES and HERP form a heterodimer and cooperate for transcriptional repression. The identification of the HERP family as a Notch effector that cooperates with HES/E(spl) family has opened a new avenue to our understanding of the Notch signaling pathway.

Animals↗