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PubMed2000

Genomic characterization of the human heterotrimeric G protein alpha, beta, and gamma subunit genes.

Heterotrimeric guanine nucleotide binding proteins (G proteins) transduce extracellular signals received by transmembrane receptors to effector proteins. Each subunit of the G protein complex is encoded by a member of one of three corresponding gene families. Currently, 16 different members of the alpha subunit family, 5 different members of the beta subunit family, and 11 different members of the gamma subunit family have been described in mammals. Here we have identified and characterized Bacterial Artificial Chromosomes (BACs) containing the human homologs of each of the alpha, beta, and gamma subunit genes as well as a G alpha11 pseudogene and a previously undiscovered G gamma5-like gene. The gene structure and chromosome location of each gene was determined, as were the orientations of paired genes. These results provide greater insight into the evolution and functional diversity of the mammalian G protein subunit genes.

Amino Acid Sequence↗
PubMed2000

Genetic analysis of ETS genes in C. elegans.

The recent completion of the Caenorhabditis elegans genome has revealed that this nematode worm has 10 members of the ETS gene family. Isolation and analysis of C. elegans mutants and subsequent screens to identify interacting genes can proceed very quickly in this model organism. Molecular genetic analysis of the receptor tyrosine kinase-Ras-MAP kinase signaling pathway in C. elegans identified the ETS family transcription factor Lin-1 as a nuclear effector of this evolutionarily conserved signal transduction pathway. Here we review classical genetic approaches used to discover the role of Lin-1 in the Ras-MAP kinase signaling pathway and describe new technologies that can be applied to the analyses of signaling pathways and transcription factor regulatory networks in C. elegans.

Amino Acid Sequence↗
PubMed1982

Characterization of H-2Db antigens implies haplotype differences in the number of H-2 molecules expressed.

Investigation of the molecular heterogeneity of H-2Db region antigens by using monoclonal antibodies and complex alloantisera has yielded evidence for the existence of only one gene product in this region. Sequential immunoprecipitation and isoelectric focusing analysis suggest that the private H-2.m2 and public H-2.m64 specificities defined by monoclonal or alloantibodies are present on the same molecule. Blocking studies with these reagents indicate these specificities represent two determinants spatially separated on the H-2Db molecule. Functional studies suggest that effector T cells may be generated against both of these determinants or closely associated epitopes, but the majority of the T cells recognize an epitope associated with or identical to the private specificity H-2.m2. Studies of the D region-encoded products of haplotypes besides H-2b have shown two or more distinct molecules can be detected by anti-H-2.m64 in both the H-2d and H-2q haplotypes. The presence of H-2.m64 on a single Db molecule is unique and gives further evidence for the lack of other gene products encoded in this region. Speculations based on the molecular heterogeneity of the D region gene products are made concerning the evolution and genetic organization of H-2 genes.

Animals↗
PubMed1998

The DNA replication and damage checkpoint pathways induce transcription by inhibition of the Crt1 repressor.

We have identified the yeast CRT1 gene as an effector of the DNA damage and replication checkpoint pathway. CRT1 encodes a DNA-binding protein that recruits the general repressors Ssn6 and Tup1 to the promoters of damage-inducible genes. Derepression of the Crt1 regulon suppresses the lethality of mec1 and rad53 null alleles and is essential for cell viability during replicative stress. In response to DNA damage and replication blocks, Crt1 becomes hyperphosphorylated and no longer binds DNA, resulting in transcriptional induction. CRT1 is autoregulated and is itself induced by DNA damage, indicating the existence of a negative feedback pathway that facilitates return to the repressed state after elimination of damage. The inhibition of an autoregulatory repressor in response to DNA damage is a strategy conserved throughout prokaryotic and eukaryotic evolution.

Animals↗
PubMed1998

Evolutionary variation of immunoglobulin mu heavy chain RNA processing pathways: origins, effects, and implications.

Immunoglobulins (Ig) can occur in two physical forms, soluble (secreted) and membrane bound. The soluble form is secreted from B cells, and is present in the blood and other fluids where it plays a role as an immune effector molecule. The membrane-bound form of the Ig molecule is inserted into the B-cell membrane, where it serves as a receptor for antigen. The function of the membrane-bound Ig as a receptor for antigen requires additional accessory molecules, the membrane Ig plus accessory molecules are referred to, collectively, as the B-cell receptor (BCR) complex. The secreted and membrane-bound forms of an Ig result from alternative patterns of RNA processing of the primary transcript from the heavy chain gene. IgM is the only class of Ig known to be conserved in all vertebrate species (perhaps exclusive of the agnathan fish). While the structure of the IgM heavy (mu) chain gene has been highly conserved in vertebrate evolution, the patterns of alternative RNA processing of the mu transcript show surprising diversity. In particular, the bony fish (teleosts) produce membrane mu-chain message by a splicing pathway that is quite different from that seen in other vertebrates; it results in the production of membrane IgM that lacks the C mu 4 domain. How this unusual RNA splicing pattern could have evolved and its implications for the function of the BCR in the bony fishes are considered here.

Animals↗
PubMed1983

The T-cell receptor mediating restrictive recognition of antigen.

Four facts characterize restrictive recognition of antigen. First, in large measure, allele-specific determinants on R are recognized when R is functioning either as a restricting element (RL) or as an allo-target (or even xeno-target) (RF). Second, there is a high frequency of virgin antigen-responsive t cells with alloreactivity, i.e. anti-RF. Third, there is a strict relationship between the class of effector function and the class of RL recognized (restrictive recognition of antigen, XF) but a relaxed relationship between class of effector function and class of RF recognized (alloreactivity). Fourth, the effector T cell functions anti-RL-dependently when XF is the target (restrictive recognition of antigen) and anti-RL-independently when RF is the target (alloreactivity). From these facts are derived the following conclusions. The T cell uses a dual recognitive, single receptor (Model I, Figure 1). A single germ-line VT locus specifying anti-allele-specific recognition of species R encodes both the anti-R and the anti-X combining sites. A "learning" process (occurring in the thymus) is required to establish the restriction specificity (anti-RL) as well as the effector function/class of RL relationship. The repertoire is derived by somatic mutation of all germ-line VT genes specifying anti-RF (Model IA, Table 3 and Figure 9). Given Model IA (Table 3 and Figure 9), we can account further for the existence of an extensive polymorphism of R and minimal polygeneism, for the high frequency of crossreactivity between anti-XF and RF, and for the physiology and genetics of cell-cell communication in immune responsiveness.

Animals↗
PubMed2001

Type IV secretion: intercellular transfer of macromolecules by systems ancestrally related to conjugation machines.

Bacterial conjugation systems are highly promiscuous macromolecular transfer systems that impact human health significantly. In clinical settings, conjugation is exceptionally problematic, leading to the rapid dissemination of antibiotic resistance genes and other virulence traits among bacterial populations. Recent work has shown that several pathogens of plants and mammals - Agrobacterium tumefaciens, Bordetella pertussis, Helicobacter pylori and Legionella pneumophila - have evolved secretion pathways ancestrally related to conjugation systems for the purpose of delivering effector molecules to eukaryotic target cells. Each of these systems exports distinct DNA or protein substrates to effect a myriad of changes in host cell physiology during infection. Collectively, secretion pathways ancestrally related to bacterial conjugation systems are now referred to as the type IV secretion family. The list of putative type IV family members is increasing rapidly, suggesting that macromolecular transfer by these systems is a widespread phenomenon in nature.

Bacterial Proteins↗
PubMed1978

Cytotoxic T-cell responses in mice infected with influenza and vaccinia viruses vary in magnitude with H-2 genotype.

Secondary effector T-cell populations generated by cross-priming with heterologous influenza A viruses operate only in H-2K or H-2D compatible situations, when assayed on SV40-transformed target cells infected with a range of influenza A viruses. The H2-Kb allele is associated with a total failure in the generation of influenza-immune cytotoxic T cells, though this is not seen for the primary response to vaccinia virus. In both influenza and vaccinia development of effector T cells operating at H-2Db is greatly depressed in B10.A(2R) (kkkddb) and B10.A(4R) (kkbbbb), but not in B10 (bbbbbb), mice. However, there is no defect in viral antigen expression at either H-2Kk or H-2Db in B10.A(2R) target cells. This apparently reflects some inadequacy in the stimulator environment, as (A/J X B6) F1 T cells can be induced to respond at H-2Db when exposed to vaccinia virus in an irradiated B6 but not in a B10.A(4R) recipient. The present report, together with the accompanying paper by Zinkernagel and colleagues, records the first rigorous demonstration of both a nonresponder situation and a probable Ir-gene effect for conventional infectious viruses. Possible implications for the evolution of H-2 polymorphism and mechanisms of Ir gene function are discussed.

Animals↗
PubMed2000

The ced-8 gene controls the timing of programmed cell deaths in C. elegans.

Loss-of-function mutations in the gene ced-8 lead to the late appearance of cell corpses during embryonic development in C. elegans. ced-8 functions downstream of or in parallel to-the regulatory cell death gene ced-9 and may function as a cell death effector downstream of the caspase encoded by the programmed cell death killer gene ced-3. In ced-8 mutants, embryonic programmed cell death probably initiates normally but proceeds slowly. ced-8 encodes a transmembrane protein that appears to be localized to the plasma membrane. The CED-8 protein is similar to human XK, a putative membrane transport protein implicated in McLeod Syndrome, a form of hereditary neuroacanthocytosis.

Alleles↗
PubMed1997

An evolutionarily conserved domain in a subfamily of Rabs is crucial for the interaction with the guanyl nucleotide exchange factor Mss4.

Mss4 is a guanine nucleotide exchange factor that specifically binds to, and promotes GDP-GTP exchange on, a subset of the Rab GTPases (Burton, J. L., Burns, M. E., Gatti, E., Augustine, G. J., and De Camilli, P. (1994) EMBO J. 13, 5547-5558). In order to identify the domain(s) of the GTPase that is important for this interaction, protein chimeras were constructed between Rab3a, which binds Mss4, and Rab5a, which does not bind Mss4. We have identified the amino-terminal portion of Rab3a as the Mss4-binding region, with the effector domain being critically required for binding and the flanking regions further enhancing the interaction. Sequence comparisons have revealed that Mss4-binding Rabs share more homology with each other than with Rabs that do not bind Mss4. The region of highest homology between these Rabs, which defines them as members of the same evolutionary branch within the Rab subfamily, coincides with the domain shown here to be critical for Mss4 binding. A mutation in the zinc-binding domain of Mss4 (Mss4 D96H), a region that is highly conserved between Mss4 and its yeast homologue Dss4, completely abolished its property to bind to, and promote GDP-GTP exchange on, Rab3a. Thus, the preservation of the Mss4/Dss4-GTPase interaction appears to have been a critical factor in the evolution of this subset of Rab proteins.

Amino Acid Sequence↗
PubMed1997

[Modulation of inflammatory cells in helminth infections].

In this review, different mechanisms by which helminthic parasites modulate the activities of inflammatory cells are considered. Examples are presented of parasitic products interfering with lymphocytes and their products such as antibodies, then modifying both regulation and effector response of the immune system. Furthermore, examples of interference on the complement system are illustrated. Parasites such as Ancylostoma caninum produce factors such as the neutrophil inhibitory factor (NIF) capable of inhibiting the neutrophil-endothelium adhesion, whereas Trichinella spiralis produces a glycoprotein, the 45gp, which inhibits different neutrophil functions. Parasites are also able to modulate the function of the monocytes-macrophages which in some infections play a crucial role; the modulation of NO synthesis is also relevant to the host-parasite relationship. Finally, the different anti-oxidant systems of helminthic parasites are described. The comprehension of such evasion mechanisms of the immune response is necessary to develop vaccines and new drugs, but it is also useful to clarify the contribution of parasites to immune system evolution.

Animals↗
PubMed2000

Bicarbonate accelerates assembly of the inorganic core of the water-oxidizing complex in manganese-depleted photosystem II: a proposed biogeochemical role for atmospheric carbon dioxide in oxygenic photosynthesis.

The proposed role for bicarbonate (HCO(3)(-)) as an intrinsic cofactor within the water-oxidizing complex (WOC) of photosystem II (PSII) [Klimov et al. (1997) Biochemistry 36, 16277-16281] was tested by investigation of its influence on the kinetics and yield of photoactivation, the light-induced assembly of the functional inorganic core (Mn(4)O(y)Ca(1)Cl(x)) starting from the cofactor-depleted apo-WOC-PSII center and free Mn(2+), Ca(2+), and Cl(-). Two binding sites for bicarbonate were found that stimulate photoactivation by accelerating the formation and suppressing the decay, respectively, of the first light-induced assembly intermediate, IM(1) [apo-WOC-Mn(OH)(2)(+)]. A high-affinity bicarbonate site (K(D) </= 10 microM) stimulates both the rate of recovery of O(2) evolving centers and decreases (by a factor of 1.2-3) t(lag), the time for formation of IM(1). This stimulation involves enhanced binding of the initial Mn(2+) and occurs only at concentrations of Mn(2+) at or below the stoichiometric requirements for water oxidation (</=4 Mn/PSII) and disappears above 4 Mn/PSII. The absence of an effect from added bicarbonate on photoactivation kinetics and yield at saturating concentrations of Mn(2+) and Ca(2+) may be due to the availability of atmospheric bicarbonate dissolved in the buffers (approximately 4 microM at pH 6.0) sufficient for photoactivation. The second bicarbonate site also stimulates the rate of formation of IM(1) but has much lower affinity (K(D) approximately millimolar) and becomes observable only at low concentrations of Ca(2+) that are limiting for photoactivation. This stimulation effect appears to occur by complexation of free Ca(2+), thereby reducing its activity in competing with Mn(2+) in the formation of IM(1). Bicarbonate had no effect on the calcium effector site responsible for the rate-limiting dark step of photoactivation (Ca(2+) binding to IM(1)). Four interpretations of the high-affinity bicarbonate effect may be advanced as testable hypotheses: bicarbonate may (1) act as an integral cofactor within the WOC (possible ligand to the first Mn), (2) act as a Bronsted base to accelerate proton release during formation of either the dark precursor [apo-WOC-Mn(OH)(+)] or IM(1) [apo-WOC-Mn(OH)(2)(+)], (3) directly deliver one or more hydroxide ions during formation of the latter two species (with release of CO(2)), or (4) act as a membrane-soluble anion that electrostatically elevates the local concentration of Mn(2+) in PSII. These results support a possible biogeochemical role for bicarbonate in the evolution of the first oxygenic photosynthetic organism. An improvement in the illumination method for photoactivation is presented in which light flashes of increasing duration are used to extend the pre-steady-state lag phase and to suppress photoinhibition, thereby improving the accuracy of t(lag) determination.

Atmosphere↗
PubMed2001

Alterations in T cell phenotype and human immunodeficiency virus type 1-specific cytotoxicity after potent antiretroviral therapy.

Cytotoxic T lymphocytes (CTLs) are an important defense against human immunodeficiency virus (HIV) type 1 but ultimately fail to control infection. To determine whether more efficient sustained immunity is induced by suppressing replication, the evolution of T cell phenotypes and HIV-specific CD8+ lymphocytes was prospectively investigated in 41 patients initiating combination therapy. Suppression of viremia to <200 copies/mL was associated with increases in naive cells (CD45RA+62L+) and declines in activated T cells (CD95+ cell counts and CD38+ HLA-DR+). HIV-specific tetramer-staining CD8+ T cells were detected in 6 of 10 HLA-A*0201-positive persons, which declined in 5 with treatment. CTL precursor frequencies were markedly consistent before and after treatment. Eight (72%) of 11 recognized > or =1 immunodominant epitope, representing either a new or an increased CTL response after treatment. Thus, activated CD8+ T cells, including those recognizing immunodominant epitopes, decline with combination therapy. However, the overall level of antigen-specific cells that are capable of differentiating into effectors remains stable, and the recognition of new epitopes may occur.

Anti-HIV Agents↗
PubMed1996

Identification of a novel Rac1-interacting protein involved in membrane ruffling.

The Rac GTP binding proteins are implicated in actin cytoskeleton-membrane interaction in mammalian cells. In fibroblast cells, Rac has been shown to mediate growth factor-induced polymerization of actin to form membrane ruffles and lamellipodia. We report here the isolation of a noval Rac1-interacting protein, POR1. POR1 binds directly to Rac1, and the interaction of POR1 with Rac1 is GTP dependent. A mutation in the Rac1 effector binding loop shown to abolish membrane ruffling also abolishes interaction with POR1. Truncated versions of POR1 inhibit the induction of membrane ruffling by an activated mutant of Rac1, V12Rac1, in quiescent rat embryonic fibroblast REF52 cells. Furthermore, POR1 synergizes with an activated mutant of Ras, V12Ras, in the induction of membrane ruffling. These results suggest a potential role for POR1 in Rac1-mediated signaling pathways.

Adaptor Proteins, Signal Transducing↗
PubMed1983

Sequence homology between Lac and Gal repressors and three sugar-binding periplasmic proteins.

Many proteins consist of several independent folding units or domains, each specifying a different function. Repressor proteins such as Lac or lambda cI carry small N-terminal domains which recognize DNA sequences and larger C-terminal domains which are required for effector recognition and/or oligomerization. The native periplasmic metabolite-binding proteins consist of short membrane-recognizing signal sequences and larger C-terminal metabolite-binding domains which also recognize membrane-bound proteins involved in transport and chemotaxis. The DNA-recognizing domains of many repressors are homologous, as are the sugar-recognizing periplasmic proteins. Here I demonstrate that the sugar-binding domains of the Lac and Gal repressors are homologous with the sugar-binding domains of three periplasmic proteins.

Amino Acid Sequence↗
PubMed1989

Stathmin is a major phosphoprotein and cyclic AMP-dependent protein kinase substrate in mouse brain neurons but not in astrocytes in culture: regulation during ontogenesis.

Stathmin is a ubiquitous soluble protein (Mr approximately 19,000; pI approximately 6.2-5.5) whose phosphorylation is associated with the intracellular mechanisms involved in the regulations of cell differentiation and functions by extracellular effectors. It is present in various tissues and cell types and has several nonphosphorylated and increasingly phosphorylated forms, and it is particularly abundant in brain. Very high concentrations of stathmin were also detected in mouse embryo striatal neurons grown in primary culture, whereas stathmin was barely detectable in astrocytes from the same source. Stathmin appeared in neurons as a major substrate for protein phosphorylation and, in particular, for the cyclic AMP (cAMP)-dependent protein kinase, because its phosphorylation was stimulated by cAMP in cell-free preparations and in intact cells by forskolin, a potent activator of adenylate cyclase. During brain ontogenesis, stathmin was first detected at embryonic day 12; its concentration increased until birth and then decreased from postnatal day 10 to adulthood. In parallel, its molecular forms shifted from the least phosphorylated to the more phosphorylated ones. This result may reflect the evolution of the activity of stathmin during development and the subsequent maturation of the brain. In conclusion, our results substantiate the likely role of stathmin as an intracellular relay of extracellular regulations, as they point out its specific importance related to neuronal functions and brain differentiation.

1-Methyl-3-isobutylxanthine↗
PubMed1990

Quantum mechanics and cellular information processing: the self-assembly paradigm.

Biological cells have greater information processing efficiency than the programmable computers used to model them. In part this is due to the larger number of interactions that can contribute to function. General arguments suggest that systems in which quantum features play a prominent role are more powerful than classical physical-dynamical analogs. A hypothetical model, involving macromolecular self-assembly, is used to illustrate how the parallelism inherent in the quantum mechanical wave function could play a role in cellular pattern processing. Signals impinging on the external membrane of the cell trigger the release of specifically shaped macromolecules. These aggregate into a mosaic shape features that reflect different groupings of the signal input patterns. The shape features are in turn read out and connected to effector actions by adaptor molecules. The self-assembly model fits into a more general hierarchical scheme of biological information processing in which macroscopic signals are transduced to mesoscopic and then microphysical representations, processed largely at the microphysical level, and then amplified for macroscopic action. The physical dynamics are controlled by proteins and other macromolecules that are molded through the evolutionary process of variation and selection. The organizational requirements for evolutionary moldability and for efficient information processing function are completely consistent. They include high dimensionality, multiplicity of weak interactions, and hierarchical-compartmental structure.

Biological Evolution↗
PubMed2026

Integrative single-cell and genomic analysis reveals NMB as a driver of metastatic adaptation in esophageal squamous cell carcinoma via metabolic rewiring and immune evasion.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) has high mortality, and metastasis is the leading cause of patient death. Neuromedin B (NMB) promotes tumor development in various cancers, yet its role in ESCC metastasis remains unclear. METHODS: We integrated single-cell transcriptomic data from matched primary and metastatic ESCC lesions (GSE309392) with bulk transcriptomic cohorts from TCGA and GSE53624. In silico gene perturbation, ligand-receptor communication analysis, and single-cell prognostic model construction were performed, followed by functional validation through siRNA-mediated NMB knockdown in TE-1 and KYSE30 cell lines. RESULTS: NMB was identified as a key gene enriched in metastatic ESCC lesions, and its high expression was associated with coordinated upregulation of oxidative phosphorylation pathway genes and aldo-keto reductase family antioxidant enzymes (AKR1C1, AKR1C2, AKR1B10). Genomic analysis revealed that NMB-high tumors carried a higher clonal mutation burden and a markedly increased frequency of NFE2L2 activating mutations (23% vs. 8%, P = 0.04). In silico knockout and correlation analysis identified AKR1C1 as a downstream effector of NMB. NMB expression was negatively correlated with CD8+ T cell and activated NK cell infiltration. CellChat analysis revealed communication between NMB-positive cells and monocytes via the TGM2-ADGRG1 axis, and specifically detected IFNG signaling. In the single-cell prognostic model, NMB-positive cells accounted for 50% of the high-risk group but only 20% of the low-risk group. TCGA-based survival analysis demonstrated that high NMB expression was associated with shorter overall survival (HR = 2.98, P = 0.03). In vitro NMB-targeted RNA interference markedly inhibited proliferation, colony formation, and migration in TE-1 and KYSE30 cells. CMap screening identified the endothelin-PDE5-cGMP axis as a potential therapeutic target. CONCLUSION: NMB serves as a key driver of metastatic adaptation in ESCC, conferring a survival advantage to tumor cells during metastatic colonization through genomic evolution and immune remodeling, with metabolic adaptation as a downstream consequence of genomic alterations.

NMB↗