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PubMed1983

[Computer bank of amino acid sequences of protein hormones. Comparative analysis of the sequences in pro-opio-melanocortin, proenkephalin and prodynorphin: detection of phorphin--the 4th repeating peptide in prodynorphin].

Using a BESM-6 computer, a computer system for accumulation and comparative analysis of amino acid sequences (AS) of protein-peptide hormones and their precursors (the so-called computer bank of protein hormone AS) was developed. A Fortran-based program designed for construction of correspondence schemes of AS and their local similarity profiles was elaborated. In combination with the previous programs this system allows a rapid inclusion of the newly deciphered sequences into the corresponding homologous groups, thus complementing the correspondence scheme and specifying the evolution profiles. A comparative analysis of AS in proopiomelanocortin (POMC), proenkephalin (PENK) and prodynorphin (PDIN) revealed evolutionary-conservative and variable sites. The conservative sites of AS are active centers of the hormones. The leu-enkephalin analog, phorphin, the fourth repeating peptide of this precursor, was detected in prodynorphin, which, similar to beta-neo-endorphin, dynorphin and rimorphin may possess a biological activity. The similarity of the effector sites of the melanotropin sequence from POMC to the met-enkephalin sequence from PENK and leu-enkephalin sequence from PDIN as well as to gastrin and cholecystokinin was established. This may suggest that the hormone-receptor complexes in target organs of these hormones are also similar.

Amino Acid Sequence↗
PubMed1995

Role of multiple cellular proteases in the execution of programmed cell death.

A family of mammalian homologues of the Caenorhabditis elegans cell death protein Ced-3 has been recently discovered. These mammalian proteins encode novel cysteine proteases with homology to the interleukin-1 beta converting enzyme (ICE). Although several studies support a role for one or more of these proteases in mediating apoptosis, their mechanism of action is far from understood. The presence of multiple mammalian ICE-like proteases, with apparently similar apoptotic function indicates that, despite its conservation during evolution, the cell death pathway is much more complex in mammals than in the worm. In addition to ICE-like proteases, several other proteases of different cleavage specificities have been implicated in apoptosis. There is now a growing body of evidence suggesting that apoptosis involves the activation of a cascade of proteases. This article summarises the presently available evidence and discusses how multiple proteases might be required in the effector phase of cell death.

Animals↗
PubMed1993

Evolution of the therapeutic use of new monoclonal antibodies.

Peptide or carbohydrate epitopes resulting from aberrant glycosylation, receptors for growth, and differentiation signals have recently been reexamined as candidates for monoclonal antibody-guided therapy. Microdistribution studies have demonstrated the limited penetration of radiolabeled antibodies in tumors. Increased tumor capillary permeability has been obtained by pretreatment with cytokines or by exploitation of monoclonal antibodies against tumor endothelial cells. The use of monoclonal antibodies for combined therapies based on different rationales (multiple monoclonal antibodies, monoclonal antibodies plus cytokines, and monoclonal antibodies plus drugs) is a recent development, and the retargeting of effector cells using hybrid monoclonal antibodies can be considered an extension of this approach. A major driving force in the field of immunotoxins today is represented by progress in protein engineering. Genes encoding various toxins have been cloned, and novel molecules with more desirable biologic properties have been produced. Also, genetic engineering techniques help in overcoming the major limitation in the clinical use of rodent monoclonal antibodies, ie, human antiimmunoglobulin response.

Animals↗
PubMed1989

The sympatho-adrenal tone and reactivity in human hypertension.

In the last two decades, remarkable advances have permitted a better understanding of the modulation of sympathetic tone and reactivity at the sympathetic nerve and at the effector cell levels. In man, several indirect approaches have permitted to suggest the possibility of increased sympathetic nerve activity and reactivity in an important subgroup of essential hypertensive patients. The demonstration of significant correlations between circulating levels of sympathetic transmitters and various parameters of cardiovascular functions supports the hypothesis of a participation of the sympathetic system in the maintenance of an elevated blood pressure in those patients. Moreover, several experimental evidences have indicated that the sensitivity of cardiovascular effector cells may be altered in hypertensive patients. The blunted beta receptor responsiveness and the normal or enhanced alpha receptor responsiveness which were observed suggest the possibility of an imbalance between adrenergic receptor functions in hypertension, which may explain the preferential alpha 1 modulation of blood pressure through changes in peripheral resistance in hypertensive patients. Such an abnormality could contribute to the development of cardiac and vascular wall hypertrophy during the evolution of hypertension. These studies therefore suggest that a variety of sympathetic dysfunctions could play a role in the development, maintenance and evolution of human essential hypertension.

Adrenal Glands↗
PubMed1981

Phylogeny of NK cell reactivity against human and nonhuman primate lymphoblastoid cell lines: evolving and conserved target antigens.

Both human and nonhuman primate natural killer (NK) cells display little or no killing against allogeneic B lymphoblastoid cell lines. However, the same B cell lines are killed in baboon-human (B alpha H) or human-baboon (H alpha B) xenogeneic combinations. Competition-inhibition experiments indicate that the xenogeneic determinants recognized by NK cells are found principally if not exclusively on B rather than T target cells. Cell lines from closely related chimpanzee or orang-utan species can block some killing of human target cells, but lines from more distantly related species including gibbon, macaque, baboon, and marmoset do not inhibit cytotoxicity. This suggests that some NK target structures are susceptible to evolutionary change. Gibbon or marmoset lines infected with Epstein Barr virus (EBV) do not block killing, suggesting that host rather than viral determinants are being recognized. In contrast to the foregoing pattern, 2 cell lines derived from the same baboon differed in susceptibility to NK lysis irrespective of the effector cell species. The viral producer line 13CB-1 was more susceptible to lysis than its viral nonproducer partner 26CB-1. Thus, some NK target antigens may be highly conserved whereas others evolve with the species.

Animals↗
PubMed1990

Similarities and differences between human and rat hexokinases type I.

The intracellular distribution and several properties of hexokinases type I purified to homogeneity from human placenta and rat brain were compared. The specific activity of the human enzyme was 190 +/- 5 U/mg protein; 140 +/- 5 U/mg protein that of the rat hexokinase. Comparative peptide mapping after limited tryptic digestion indicates a similar domain structure, however analogous experiments performed in the presence of substrates or effectors of the enzyme provide evidence of significant differences among hexokinases. Similarly, immunological studies with polyclonal and monoclonal antibodies while confirming some common epitopes also disclose important differences that cannot be expected on the basis of amino acid composition and of an in vivo identical function. These results are consistent with suggestions by several investigators that amino acid substitutions in mammalian hexokinases have occurred at a relatively fast rate during hexokinase type I evolution.

Amino Acid Sequence↗
PubMed1988

Hemoglobins of reptiles. The primary structures of the alpha I- and beta I-chains of common iguana (Iguana iguana) hemoglobin.

The primary structures of alpha I- and beta I-chains from the hemoglobins of the Common Iguana (Iguana iguana) are presented. The globin chains were separated on CM-cellulose in 8 M urea buffer. The amino-acid sequences were established by automatic Edman degradation of the native chains, the tryptic peptides and a peptide obtained by cyanogen bromide cleavage. The sequences are compared with human hemoglobin. Amino-acid replacements at positions critical for structure and function of the hemoglobin are discussed. The requirements for binding of ATP and also of DPG as allosteric effectors at the beta-chains seem to be fulfilled. Comparison of the alpha-chains with those of the Viper (Vipera aspis) shows 66 amino-acid substitutions. This number is in the same order of magnitude as the ones found by comparison with alpha-chains of crocodiles and mammals as well as with alpha A-chains of a turtle and birds. This result points towards a period of independent evolution of the reptile lines leading to the Common Iguana on one hand and to the Viper on the other. This time span is comparable to the one separating mammals from reptiles.

Amino Acid Sequence↗
PubMed1981

[Hemoglobins, XLII: Studies on the hemoglobin of the greylag goose (Anser anser). The primary structures of the alpha- and beta-chains of the main component (author's transl)].

The alpha- and beta-chains of the main component of hemoglobin of the greylag goose (Anser anser) were isolated. For determination of the primary structure of hemoglobin, the chains were cleaved and the cleavage products isolated. The chains and peptides were degraded automatically in the sequenator: the complete primary structure of the alpha-and beta-chains was obtained and compared with the human adult hemoglobin. Comparison with human sequences show 1 substitutions in the alpha-chain and 44 in beta-chain. The mutations are discussed. The alpha-chains contain no tryptophan, only one methionine and two cysteines. Seven alpha 1 beta 1-contacts and one alpha 1 beta 2-oxy- and deoxy-contact are altered. In the beta-chains two acidic amino acids are eliminated. This is probably the reason for the more basic character of the greylag goose hemoglobin. The contact points of the allosteric effector (inositol pentaphosphate in case of birds, 2,3-diphosphoglycerate in case of mamals) with the beta-chains are identical in chicken and greylag goose, two more than in the human beta-chains. Six alpha 1 beta 1-contacts and one hem-contact are changed. This work forms a basis to allow comparison of the functions of several bird hemoglobins and for further studies of bird hemoglobins and for further studies of evolution and systematics of birds.

Amino Acid Sequence↗
PubMed1992

Serotonin receptor 1c gene assigned to X chromosome in human (band q24) and mouse (bands D-F4).

In the mammalian nervous system, serotonin (5-hydroxytryptamine) binds to distinct cell surface receptor subtypes that are defined by their ligand binding and effector-coupling properties. The 5HT1c receptor is a G-protein coupled receptor that stimulates phospholipase C-catalyzed hydrolysis of phosphatidylinositol bisphosphate, leading to the mobilization of intracellular calcium and to the activation of protein kinase C. By using somatic cell hybrid analysis and FISH, we have mapped the HTR1C locus to the human X chromosome, band q24 and to the mouse X chromosome region D-F4. Comparison of these map positions offers new insights into the evolution of human and murine X chromosomes. Since HTR1C is expressed in certain parts of the central nervous system and abnormal function of the serotoninergic system has been implicated in affective disorders, obsessive-compulsive disorder and epilepsy, establishing the precise map position of HTR1C is an important first step toward evaluating this locus as a candidate for mutations in these syndromes and in X-linked mental disorders.

Animals↗
PubMed1994

Modelling and simulation of Rosenberg-type adoptive cellular immunotherapy.

A mathematical model is developed to describe the process of adoptive cellular immunotherapy (ACI) using the scheme of Rosenberg and other investigators. The model exhibits the dynamics of tumour cells as well as the time evolution of the tumoricidal immunocytes, such as ex vivo interleukin-2 (IL-2) expanded natural killer (NK) cells, lymphokine activated killer (LAK) cells, tumour derived activated cells (TDAC), and interferon-gamma (IFN-gamma) activated killer monocytes (AKM). The model is described mathematically by a system of nonlinear functional-differential equations. Computer simulations based on the model equations are performed using parametric configurations analogous to the protocols used in the clinical trials. The model elucidates explicitly the effects of time delays, effector immunocyte-to-tumour cell ratio, tumour growth parameters, and other critical variables on the prognosis, and the therapeutic efficacy of adoptive cellular immunotherapy.

Humans↗
PubMed1985

Suppression in Xenopus laevis: thymus inducer, spleen effector cells.

Studies were carried out on suppressor function in the amphibian Xenopus laevis, the South African clawed toad. Suppression by the thymus of haemagglutinin (HA) production by spleen is antigen-dependent, partially specific and not MHC-restricted in this species (Ruben, Buenafe & Seivert, 1983). Three questions were considered in this study. Does the thymus effect suppression by stimulating peripheralized spleen effector cells, or do effector cells reside within the thymus? Do macrophages participate in the induction and/or expression of thymus-dependent suppressor function? Can thymus suppressor and helper functions be distinguished by using irradiation treatment? The capacity of immunized thymus to suppress HA when co-cultured with spleen fragments from immunized, cyclophosphamide (CyP)-injected animals was tested. Immunized thymus failed to suppress the high levels of HA production by spleen fragments from CyP-treated, immunized donors. Colloidal carbon injection resulted in blockade of macrophage function, and both the capacity of thymuses to suppress and of spleens to be suppressed in co-cultures. Finally, the effect of thymus exposure to gamma-irradiation in vitro was tested using autogeneic thymus/spleen combinations. This enabled the visualization of thymic helper function, which is MHC-restricted in Xenopus (Bernard et al., 1981). Four dosages of irradiation were tested after antigen challenge. The highest HA titres were produced by spleen co-cultures with thymuses which had received 1000 rads. We conclude that suppression of HA production in spleen is not the result of thymus suppressor effector cells, but that suppressor function is mediated by thymus inducer cells which stimulate suppressor effectors in spleen. Both the thymic inducers and effectors in the spleen are sensitive to CyP and macrophage blockade. Our studies further suggest that we are able to distinguish between the thymic functions of help and suppression in Xenopus by taking advantage of their differential sensitivities to irradiation. While it has been postulated, on other grounds, that suppression was one of the earliest thymic regulatory functions to have evolved (L.N. Ruben & R.H. Clothier, submitted), here we suggest the presence of sequential activities of more than one cellular subset, as early in evolution as the primitive anuran (tail-less) amphibia.

Animals↗
PubMed1986

The T4 glycoprotein is a cell-surface receptor for the AIDS virus.

Taken together, our studies suggest a mechanism of AIDS virus infection that initially involves the specific association of the AIDS virus with T4 molecules on the cell surface. This association does not require additional T-cell-specific molecules and can be demonstrated on both B lymphocytes and epithelial cell lines. The T4-AIDS virus complex is likely to be internalized in endosomes via receptor-mediated endocytosis. The virus can then fuse with the vacuolar membrane, releasing the viral nucleocapsid into the cytoplasm to undergo uncoating. Viral replication does not appear to require the environment of a T lymphocyte because active infection is also observed in human T4+ B lymphocytes and epithelial cell lines. Moreover, the T4 gene is expressed in the brain as well as in lymphocytes, providing an explanation for the dual neurotropic and lymphotropic character of the virus. In this manner, a T-lymphocyte surface protein thought to be important in mediating effector cell-target cell interactions has been exploited by a human lymphotropic virus to target the AIDS virus specifically to populations of T4+ cells.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Evolutionary implications of a new bypass activation pathway of the complement system.

The classical pathway of complement activation is a highly specific and amplifiable effector system responding to recognition of foreign antigens by antibody. It comprises a group of well characterized proteins in mammalian plasma. There are many similarities with the alternative pathway of complement activation, which suggests that they have a common evolutionary origin. Both pathways have homologous components, use related activation and regulatory mechanisms, result in the release of the anaphylatoxins C3a and C5a, and deposit C3b onto activating surfaces. This fixed C3b then becomes the focus of further immune reactions, involving either the lytic complement components or C3b receptors on effector cells. Phylogenetic data indicate that the alternative pathway is the older, and that the classical pathway evolved from it. Here Timothy Farries and colleagues review this evolutionary process and present a possible sequence of events that is suggested by recent functional data from their laboratory.

Animals↗
PubMed1992

Saccharomyces cerevisiae elongation factor 2. Genetic cloning, characterization of expression, and G-domain modeling.

The elongation factor 2 (EF-2) genes of the yeast Saccharomyces cerevisiae have been cloned and characterized with the ultimate goal of gaining a better understanding of the mechanism and control of protein synthesis. Two genes (EFT1 and EFT2) were isolated by screening a bacteriophage lambda yeast genomic DNA library with an oligonucleotide probe complementary to the domain of EF-2 that contains diphthamide, the unique posttranslationally modified histidine that is specifically ADP-ribosylated by diphtheria toxin. Although EFT1 and EFT2 are located on separate chromosomes, the DNA sequences of the two genes differ at only four positions out of 2526 base pairs, and the predicted protein sequences are identical. Genetic deletion of each gene revealed that at least one functional copy of either EFT gene is required for cell viability. Messenger RNA levels of yeast EF-2 parallel cellular growth and peak in mid-log phase cultures. The EF-2 protein sequence is strikingly conserved through evolution. Yeast EF-2 is 66% identical to, and shares over 85% homology with, human EF-2. In addition, yeast and mammalian EF-2 share identical sequences at two critical functional sites: (i) the domain containing the histidine residue that is modified to diphthamide and (ii) the threonine residue that is specifically phosphorylated in vivo in mammalian cells by calmodulin-dependent protein kinase III, also known as EF-2 kinase. Furthermore, yeast EF-2 also contains the Glu-X-X-Arg-X-Ile-Thr-Ile "effector" sequence motif that is conserved among all known elongation factors, and its GTP-binding domain exhibits strong homology to the G-domain of Escherichia coli elongation factor Tu (EF-Tu) and other G-protein family members. Based upon these observations, we have modeled the G-domain of the deduced EF-2 protein sequence to the solved crystallographic structure for EF-Tu.

Amino Acid Sequence↗
PubMed2025

MYC and p53 Alterations Cooperate through VEGF Signaling to Repress Cytotoxic T-cell and Immunotherapy Responses in Prostate Cancer.

UNLABELLED: Patients with castration-resistant prostate cancer (CRPC) are generally unresponsive to tumor-targeted treatments and immunotherapies. Genetic alterations acquired during the evolution of CRPC may affect antitumor immunity and immunotherapy responses, which could inform personalized therapeutic strategies. Using our innovative electroporation-based mouse models, we generated distinct genetic subtypes of CRPC found in patients and uncovered unique immune microenvironments. Specifically, mouse and human prostate tumors with MYC amplification and p53 disruption had weak cytotoxic lymphocyte infiltration and an overall dismal prognosis. MYC and p53 cooperated to induce tumor-intrinsic secretion of VEGF, which signaled through VEGFR2 expressed on CD8+ T cells to directly inhibit T-cell migration and effector functions. Targeting VEGF-VEGFR2 signaling in vivo remodeled the immunosuppressive prostate tumor microenvironment, leading to CD8+ T-cell-mediated primary tumor and metastasis growth suppression and significantly increased overall survival in MYC- and p53-altered CRPC. VEGFR2 blockade also led to the induction of PD-L1 in tumors and produced antitumor efficacy in combination with PD-L1 immune checkpoint blockade in multiple preclinical CRPC mouse models. Thus, these results identify a genetic mechanism of immunosuppression through VEGF signaling in prostate cancer that can be targeted to reactivate immune and immunotherapy responses in an aggressive subtype of CRPC. SIGNIFICANCE: VEGFR2 blockade inhibits VEGF-mediated T-cell suppression and potentiates the effects of PD-L1 immune checkpoint blockade to treat castration-resistant prostate cancer driven by MYC and p53 alterations.

Male↗
PubMed1992

Sensational science. Sensory Transduction: 45th Annual Symposium of the Society of General Physiologists, Marine Biological Laboratory, Woods Hole, MA, USA, September 5-8, 1991.

In the course of several days of formal and informal talks, in the idyllic setting of Woods Hole, the impression grew among many of the participants that useful common themes have emerged for comparison among sensory transduction systems. Many of these were made explicit in a talk on biophysical principles of sensory transduction by Steven Block (Cambridge, MA, USA). In one hour, Block summarized the rest of the symposium and much more, in a dazzling tour through the senses. One of his points was that all sensory transducers must fulfill common goals: detection of the signal, which involves the functions of collecting, selecting or tuning, and capture of the stimulus; amplification, to raise the signal energy (without adding noise) for transmission to other parts of the organism; adaptation or feedback, to extract behaviorally useful parts of the signal; termination, to re-prime the system for the next signal; and encoding, which puts the information in a useful form for downstream processing or effector elements. Another useful comparison was between quantum-detecting systems, such as photoreception and olfaction, where the energy of the stimulus quantum (photon or odor ligand) is large and a uniform response is desired, and noise-limited systems, such as auditory transduction or magnetoreception, where thermal noise is larger than the smallest stimuli and time-averaging helps pull the signal out of the noise. A third observation from Block was that sensory transduction systems--while often performing at physical limits--have not necessarily been perfected by the process of evolution.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1978

Target antigens of cell-mediated lympholysis discrimination of HLA subtypes by cytotoxic lymphocytes.

The evolution of HLA specificities has been toward ever-increasing refinement; one example is a subdivision of HLA-B5, the supertype specificity originally defined as 4a. HLA-B5 can now be further subdivided into Bw51 amd Bw52 by serologic means. Whereas the specificity Bw51 can be detected by specific sera, the identification of Bw52 must frequently be deduced from knowledge of B5 and Bw51, although serology has progressed rapidly. There has been no comparable development in identifying fine specificities by cellular cytotoxicity in populations. We have now found that cytotoxic effectors of exquisite specificity can be generated against Bw52 by sensitization of cells from a Bw51 donor and vice versa; Bw51 and Bw52 can in this way be recognized with equal ease. This may set a precedent for recognizing fine specificities of other HLA antigens that cannot yet be identified serologically or can be identified only imprecisely. These fine distinctions may have great relevance in allotransplantation and in understanding disease susceptibility.

Absorption↗
PubMed1987

Inhibition of SK cell activity in frogs by certain drugs and sugars.

We present similarities between mammalian natural killer (NK) cells and (anuran amphibian) frog spontaneous killer (SK) cells. A cytotoxic assay utilizing allogeneic erythrocytes as target cells was used and lysis assessed by measuring release of hemoglobin. SK effector cells, just as mammalian NK cells, are not sensitive to cycloheximide nor most simple sugars (50 mM glucose, glucose-6-phosphate, galactose, fucose, mannose). However, SK activity is inhibited by chloroquine, colchicine and mannose-6-phosphate. When SK cells were co-incubated with mammalian tumor cells, they were able to lyse only the NK-sensitive target YAC-1, but not other mammalian tumor cell targets including K562, Molt-4, Raji, P815 and EL4. Lysis of YAC-1 cells was also inhibited by colchicine and chloroquine. These results allow speculation on the evolution of cell mediated cytotoxicity since natural cytotoxic cells are present in ectothermic vertebrates.

Animals↗