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PubMed1994

A Mutant of Arabidopsis with Increased Levels of Stearic Acid.

A mutation at the fab2 locus of Arabidopsis caused increased levels of stearate in leaves. The increase in leaf stearate in fab2 varied developmentally, and the largest increase occurred in young leaves, where stearate accounted for almost 20% of total leaf fatty acids. The fatty acid composition of leaf lipids isolated from the fab2 mutant showed increased stearate in all the major glycerolipids of both the chloroplast and extrachloroplast membranes. Although the stearate content was increased, the fab2 mutant still contained abundant amounts of 18:1, 18:2, and 18:3 fatty acids. These results are consistent with the expectations for a mutation partially affecting the action of the stromal stearoyl-acyl carrier protein desaturase. Positional analysis indicated that the extra 18:0 is excluded with high specificity from the sn-2 position of both chloroplast and extrachloroplast glycerolipids. Although stearate content was increased in all the major leaf membrane lipids, the amount of increase varied considerably among the different lipids, from a high of 25% of fatty acids in phosphatidylcholine to a low of 2.9% of fatty acids in monogalactosyldiacylglycerol.

Journal Article↗
PubMed1984

New Salmonella typhimurium mutants with altered outer membrane permeability.

We describe three new classes of Salmonella typhimurium mutants with increased sensitivity to hydrophobic agents. In contrast to many previously described mutants, the phage sensitivity pattern of these mutants did not give any indication of defective lipopolysaccharide. Furthermore, they had no detectable changes in their phospholipid or outer membrane protein composition, and their growth rate and cell morphology were normal. Class B mutants were nearly as sensitive to novobiocin, fusidic acid, erythromycin, rifampin, and clindamycin as are deep rough (heptoseless) mutants; in addition they were sensitive to methicillin, penicillin (to which heptoseless mutants are resistant), gentian violet, and anionic and cationic detergents. Class A and C mutants had less sensitive, but characteristic phenotypes. None of the three classes were sensitive to serum bactericidal action. The class B mutation mapped between map positions 7 and 11 on the S. typhimurium chromosome, and the class C mutation mapped between positions 5 and 7. The map position for the class A mutation remained undefined, but it was separate from the class B and C mutations and, like those, did not correspond to any gene loci known to participate in the synthesis of major outer membrane constituents.

Bacterial Outer Membrane Proteins↗
PubMed2005

Mammalian polyhomeotic homologues Phc2 and Phc1 act in synergy to mediate polycomb repression of Hox genes.

The Polycomb group (PcG) gene products form multimeric protein complexes and contribute to anterior-posterior (A-P) specification via the transcriptional regulation of Hox cluster genes. The Drosophila polyhomeotic genes and their mammalian orthologues, Phc1, Phc2, and Phc3, encode nuclear proteins that are constituents of evolutionarily conserved protein complexes designated class II PcG complexes. In this study, we describe the generation and phenotypes of Phc2-deficient mice. We show posterior transformations of the axial skeleton and premature senescence of mouse embryonic fibroblasts associated with derepression of Hox cluster genes and Cdkn2a genes, respectively. Synergistic actions of a Phc2 mutation with Phc1 and Rnf110 mutations during A-P specification, coimmunoprecipitation of their products from embryonic extracts, and chromatin immunoprecipitation by anti-Phc2 monoclonal antibodies suggest that Hox repression by Phc2 is mediated through the class II PcG complexes, probably via direct binding to the Hox locus. The genetic interactions further reveal the functional overlap between Phc2 and Phc1 and a strict dose-dependent requirement during A-P specification and embryonic survival. Functional redundancy between Phc2 and Phc1 leads us to hypothesize that the overall level of polyhomeotic orthologues in nuclei is a parameter that is critical in enabling the class II PcG complexes to exert their molecular functions.

Animals↗
PubMed2000

Probing the interaction between inactivation gating and Dd-sotalol block of HERG.

Potassium channels encoded by HERG underlie I:(Kr), a sensitive target for most class III antiarrhythmic drugs, including methanesulfonanilides such as Dd-sotalol. Recently it was shown that these drugs are trapped in the channel as it closes during hyperpolarization. At the same time, HERG channels rapidly open and inactivate when depolarized, and methanesulfonanilide block is known to develop in a use-dependent manner, suggesting a potential role for inactivation in drug binding. However, the role of HERG inactivation in class III drug action is uncertain: pore mutations that remove inactivation reduce block, yet many of these mutations also modify the channel permeation properties and could alter drug affinity through gating-independent mechanisms. In the present study, we identify a definitive role for inactivation gating in Dd-sotalol block of HERG, using interventions complementary to mutagenesis. These interventions (addition of extracellular Cd(2+), removal of extracellular Na(+)) modify the voltage dependence of inactivation but not activation. In normal extracellular solutions, block of HERG current by 300 micromol/L Dd-sotalol reached 80% after a 10-minute period of repetitive depolarization to +20 mV. Maneuvers that impeded steady-state inactivation also reduced Dd-sotalol block of HERG: 100 micromol/L Cd(2+) reduced steady-state block to 55% at +20 mV (P:<0.05); removing extracellular Na(+) reduced block to 44% (P:<0.05). An inactivation-disabling mutation (G628C-S631C) reduced Dd-sotalol block to only 11% (P:<0.05 versus wild type). However, increasing the rate of channel inactivation by depolarizing to +60 mV reduced Dd-sotalol block to 49% (P:<0.05 versus +20 mV), suggesting that the drug does not primarily bind to the inactivated state. Coexpression of MiRP1 with HERG had no effect on inactivation gating and did not modify Dd-sotalol block. We postulate that Dd-sotalol accesses its receptor in the open pore, and the drug-receptor interaction is then stabilized by inactivation. Whereas deactivation traps the bound methanesulfonanilide during hyperpolarization, we propose that HERG inactivation stabilizes the drug-receptor interaction during membrane depolarization.

Animals↗
PubMed1996

Histidine at position 5 is the specificity "switch" between two parathyroid hormone receptor subtypes.

The PTH and PTH-related protein (PTHrP) system consists of two hormones, at least two G protein-coupled seven-transmembrane domain receptors, and at least two intracellular signal transduction pathways for each receptor. The PTH/PTHrP receptor is present in the conventional target tissues of PTH action, namely kidney and bone. Both PTH and PTHrP bind to and activate the PTH/PTHrP receptor with equal affinity and efficacy. The newly discovered receptor, termed the human (h) PTH2 receptor, has 70% homology with the PTH/PTHrP receptor, but is found predominantly in brain and pancreas. It interacts selectively with PTH and not with PTHrP. PTH and PTHrP differ in several positions, including position 5 (Ile in PTH; His in PTHrP). To define the role of position 5 in receptor selectivity, we designed and synthesized a series of hybrid analogs containing specific elements of both the PTH and PTHrP sequences. Using human cell lines stably expressing either human receptor subtype, we evaluated the biological profile of the hybrids in assays of receptor binding and action. Both point-mutated hybrids, [Ile5]PTH-(1-34) and [His5]PTH-(1-34), bind to and stimulate cAMP accumulation and the release of cytosolic free calcium in HEK293/C-21, a clonal human embryonic kidney cell line stably expressing the recombinant hPTH/PTHrP receptor. However, only [Ile5]PTHrP-(1-34), and not [His5]PTH-(1-34), binds to and stimulates cAMP accumulation and the release of cytosolic free calcium in HEK293/BP-16, a clonal human embryonic kidney cell line stably expressing the recombinant hPTH2 receptor. The segmental hybrid PTHrP-(1-14)-PTH-(15-34) binds to and activates the hPTH/PTHrP receptor, but not the hPTH2 receptor, similar to the biological profile of His5-containing ligands: PTHrP-(1-34) and [His5]PTH-(1-34). Exchanging Ile5 for His5 in the segmental hybrid produces the analog [Ile5]PTHrP-(1-14)-PTH-(15-34), which interacts with both receptor subtypes. We conclude that His5 in PTHrP is the major structural determinant of receptor subtype specificity in the hPTH/PTHrP and hPTH2 two-receptor system. The mechanism of the specificity "switch" remains to be elucidated, but may result from a subtle perturbation of the bioactive conformation and/or from a direct steric hindrance at the hPTH2 receptor-ligand interface created by histidine at position 5. The hPTH2, but not the hPTH/PTHrP, receptor can discriminate between the two hormones based on the structural differences generated at position 5.

Amino Acid Sequence↗
PubMed2000

The three subfamilies of leucine-rich repeat-containing G protein-coupled receptors (LGR): identification of LGR6 and LGR7 and the signaling mechanism for LGR7.

Glycoprotein hormone receptors, including LH receptor, FSH receptor, and TSH receptor, belong to the large G protein-coupled receptor (GPCR) superfamily but are unique in having a large ectodomain important for ligand binding. In addition to two recently isolated mammalian LGRs (leucine-rich repeat-containing, G protein-coupled receptors), LGR4 and LGR5, we further identified two new paralogs, LGR6 and LGR7, for glycoprotein hormone receptors. Phylogenetic analysis showed that there are three LGR subgroups: the known glycoprotein hormone receptors; LGR4 to 6; and a third subgroup represented by LGR7. LGR6 has a subgroup-specific hinge region after leucine-rich repeats whereas LGR7, like snail LGR, contains a low density lipoprotein (LDL) receptor cysteine-rich motif at the N terminus. Similar to LGR4 and LGR5, LGR6 and LGR7 mRNAs are expressed in multiple tissues. Although the putative ligands for LGR6 and LGR7 are unknown, studies on single amino acid mutants of LGR7, with a design based on known LH and TSH receptor gain-of-function mutations, indicated that the action of LGR7 is likely mediated by the protein kinase A but not the phospholipase C pathway. Thus, mutagenesis of conserved residues to allow constitutive receptor activation is a novel approach for the characterization of signaling pathways of selective orphan GPCRs. The present study also defines the existence of three subclasses of leucine-rich repeat-containing, G protein-coupled receptors in the human genome and allows future studies on the physiological importance of this expanding subgroup of GPCR.

Amino Acid Sequence↗
PubMed1984

Genetic control of pathogenesis of diabetes in C3H mice. Influence of the major histocompatibility complex.

Inbred strains of genetically diabetic (db/db) male mice with H-2b haplotype were heretofore found resistant to the diabetogenic action of the db mutation, whereas C3HeB/FeJ-db/db males with H-2k haplotype were susceptible. To determine whether the major histocompatibility complex was linked to diabetes predisposition, we mated C3H.SW/SnJ females (H-2b haplotype) with C3HeB/FeJ- +/db males, identified the +/db heterozygotes in the F1 generation (all H-2b/H-2k), and intercrossed these to produce F2 db/db male offspring that were classed and studied according to the three segregating H-2 genotypes. We found an accelerated diabetes pathogenesis in terms of early onset of severe hyperglycemia, destruction of pancreatic beta cells, and mortality that was not linked to H-2. Of 9 F2 male diabetics with H-2b/H-2b genotype, 14 with H-2b/H-2k genotype, and 5 with H-2k/H-2k genotype, all showed a more severe syndrome than did the grandparental-type C3HeB/FeJ-db/db males. We conclude that on the C3H inbred background, the major histocompatibility complex is not a major background modifier of the diabetes syndrome. The complexity of the results suggests residual non-H-2-related genetic variance between the two grandparental C3H stocks, with C3H.SW/SnJ females possessing diabetes susceptibility factors apparently lacking in C3HeB/FeJ (a stock bred to be free of the milk-borne mouse mammary tumor virus). Since C3H.SW/SnJ females transmitted to F2 males unknown diabetogenic factor(s) that did not appear to segregate, inheritance of a virus was suggested.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2006

Theoretical proposal: allele dosage of MAP2K4/MKK4 could rationalize frequent 17p loss in diverse human cancers.

Although aneuploidy is a global genomic abnormality present in most human cancers, the clonal selection model best explains the action of select activating mutations in oncogenes and homozygous losses of tumor-suppressor genes. Simple gene dosage changes are difficult however, to incorporate into this model, in part due to negative feedback loops that govern major cancer mutational targets (e.g., TP53, PTCH, SMAD4) and essentially preclude a haploinsufficient phenotype. The 17p conundrum may offer a clue to reconciling this difficulty: In comparison to the moderate mutation rate of TP53, many tumors have a disproportionately high frequency of loss of 17p. This discrepancy, and similar discrepancies at other sites of LOH, has long been thought to be due to the presence of undiscovered yet frequently mutated tumor-suppressor genes. However, over 15 years of searching for this grail has distributed bountiful disappointment. It is perhaps time to seriously consider an alternative explanation. Located on 17p adjacent to the TP53 gene, MKK4 is one of the most consistently mutated genes across tumor types, and is located on one of the most frequently lost arms in the human genome. We theorized that a gene dosage-dependent phenotype of MKK4 could plausibly promote the emergence of 17p LOH and thereby the probability of evolving the biallelic inactivation of TP53. Using MKK4 somatic human knockout cancer cells, we observed the proof-of-principle in the downstream gene dosage-dependent phenotypes: heterozygous and homozygous knockouts were progressively deficient in Mkk4 protein, in stress-induced phosphorylation of Jnk, and the resultant upregulation of JUN mRNA. These observations highlight a lack of compensatory regulation when gene dosage changes perturb the Jnk-Jun relationship. Consideration of gene dosage changes specifically affecting members of positive feedback loops may permit integration of the aneuploidy process into a conventional model of clonal selection in tumorigenesis.

Cell Line, Tumor↗
PubMed1975

Prophage induction and cell division in E. coli. III. Mutations sfiA and sfiB restore division in tif and lon strains and permit the expression of mutator properties of tif.

In E. coli K12, cell filamentation promoted by tif is enhanced by the lon mutation; in contrast, prophage induction and repair of UV-irradiated phage lambda, also promoted by tif, are not affected by lon. From a tif lon double mutant, "revertants" having recovered the ability to divide at 41 degrees were isolated, among which most (95%) had also lost their Lon filamentous phenotype after ultraviolet (UV) irradiation. From these 95% of revertants: (1) 94% are suppressed for the whole Tif phenotype, by additional mutations that render them deficient in DNA repair, as judged from their high UV sensitivity; some have been characterized as recA mutants. (2) 1% have recovered a control on cell division at 41 degrees or after UV irradiation by means of secondary mutations altering neither the other phenotypic properties of tif and lon, nor the repair and recombination ability of the cells: in particular, this class of "revertants" remains thermoinducible upon lysogenisation; the mutations which specifically suppress filamentation have been mapped at two loci, sfiA and sfiB, cotransducible respectively with pyrD and leu. In the remaining 5% of revertants that still exhibit an UV-induced filamentous growth, 3% can be tentatively classified as true tif+ revertants; 2% behave as tif thermodependent revertants, showing suppression of the Tif (and Lon) phenotype only at 41 degrees: 2recAts have been identified in this class. Non-lysogenic tif lon sfi and tif sfi strains remain viable during prolonged growth at 41 degrees. Under these conditions, tif expresses mutator properties, which can be conveniently analyzed in this sfi background. The action of lif, lon and sfi mutations is tentatively interpreted on the basis of a negative control of cell division specifically associated with DNA repair.

Cell Division↗
PubMed2004

[Toxicological aspects and health risks associated with hydroquinone in skin bleaching formula].

The use of hydroquinone as a cosmetic skin-bleaching agent has been forbidden since January 2001. It is now available only on prescription. The ban has been introduced because of medium-term effects such as white patches on the skin, particularly on the face (leukoderma with confetti-like depigmentation), and subcutaneous dark collections of pigment (exogenous ochonosis). Long-term effects are a possibility; cancer being the most likely. Renal adenomas and leukaemia occurred in animal experiments indicating the nephrotoxicity and carcinogenic properties of the substance. It is now known how hydroquinone and its metabolites can cause damage to DNA and inhibit apoptosis of mutated cells. The carcinogenic action of benzene is difficult to attribute to its hydroquinone metabolite. Daily use of hydroquinone causes it to accumulate in the body as absorption into the skin is faster than excretion in the urine. The use of hydroquinone as a skin-bleaching agent is accordingly unsafe and should be completely banned. Alternatives such as azaleic acid and thioctic acid (alpha-lipoic acid) are available.

Administration, Topical↗
PubMed1982

[Promoting action of tetradecanoylphorbol acetate on the phenotypic expression of the mutation for the acquisition of resistance to diphtheria toxin in cultured human cells].

Stable spontaneous mutants resistant to the protein synthesis inhibitor diphtheria toxin (DT) have been selected in human cell line eue at a very low frequency (8 x 10(-6)). We have studied in this system the effect of the promoting agent phorbol-12-myristate-13-acetate (TPA) on mutagenesis induced by benzo(a)pyrene (BP). TPA did not increase the mutation frequencies induced by BP, but it showed a trend to make shorter the expression time.

Benzo(a)pyrene↗
PubMed1994

A novel C-terminal domain in the thyroid hormone receptor selectively mediates thyroid hormone inhibition.

Resistance to thyroid hormone (RTH) action is due to mutations in the beta-isoform of the thyroid hormone receptor (TR-beta). RTH patients display inappropriate central secretion of thyrotropin-releasing hormone (TRH) from the hypothalamus and thyrotropin (TSH) from the anterior pituitary in association with abnormal peripheral tissue responses to thyroid hormone. Whether TR-beta mutations cause a selective form of RTH, which only leads to abnormal pituitary TSH secretion (PRTH), is unclear. In a patient with PRTH, a novel mutation of a conserved arginine residue adjacent to the ninth heptad of TR-beta selectively disrupts TR homodimer formation. The mutant TR displays normal or enhanced function on stimulatory thyroid hormone response elements found in peripheral tissues, but has defective function on inhibitory thyroid hormone response elements found in the TRH and TSH subunit genes and explains the PRTH phenotype. This is the first report of a mutation in a member of the nuclear receptor superfamily that selectively abolishes hormone-dependent inhibition and localizes a novel C-terminal domain necessary for this property.

Amino Acid Sequence↗
PubMedDate not supplied

[A synthetic fragment of insulin with insulin-like biological activity].

We have used computer modeling of insulin 3-D structure and experimental data about action of site point mutation on insulin activity to design functionally important domain with signaling activity and synthesized peptide than might be sufficient for the binding to insulin receptor. The designed and synthesized peptide consist of ten residues and may be obtained in two forms: oxidized and reduced (with or without disulfide bond). The synthesized decapeptide peptide represents functionally important site for binding to the insulin receptor. Amino acid residues at position 1-8 correlate with B-chain of insulin at position (B19-B26). Residues at position 9.10 correlate with A-chain at position A-10-A21. This peptide was tested with cell culture L-929 (glucose uptake) in comparison with bioactive commercial peptide (R-G-FF) and insulin. It was shown that synthesized peptide exhibit biological activity at molar concentration 0.01-1 mkM. Our results successfully demonstrate the synthetic insulin fragment have insulin-like biological activity.

Animals↗
PubMed1998

herg encodes a K+ current highly conserved in tumors of different histogenesis: a selective advantage for cancer cells?

The human ether-a-go-go-related gene (herg) encodes a K+ current (IHERG) that plays a fundamental role in heart excitability by regulating the action potential repolarization (IKr); mutations of this gene are responsible for the chromosome 7-linked long QT syndrome (LQT2). In this report, we show that in a variety (n = 17) of tumor cell lines of different species (human and murine) and distinct histogenesis (neuroblastoma, rhabdomyosarcoma, adenocarcinoma, lung microcytoma, pituitary tumors, insulinoma beta-cells, and monoblastic leukemia), a novel K+ inward-rectifier current (IIR), which is biophysically and pharmacologically similar to IHERG, can be recorded with the patch-clamp technique. Northern blot experiments with a human herg cDNA probe revealed that both in human and murine clones the very high expression of herg transcripts can be quantified in at least three clearly identifiable bands, suggesting an alternative splicing of HERG mRNA. Moreover, we cloned a cDNA encoding for IIR from the SH-SY5Y human neuroblastoma. The sequence of this cDNA result was practically identical to that already reported for herg, indicating a high conservation of this gene in tumors. Consistently, the expression of this clone in Xenopus oocytes showed that the encoded K+ channel had substantially all of the biophysical and pharmacological properties of the native IIR described for tumor cells. In addition, in the tumor clones studied, IIR governs the resting potential, whereas it could not be detected either by the patch clamp or the Northern blot techniques in cells obtained from primary cell cultures of parental tissues (sensory neurons and myotubes), whose resting potential is controlled by the classical K+ anomalous rectifier current. This current substitution had a profound impact on the resting potential, which was markedly depolarized in tumors as compared with normal cells. These results suggest that IIR is normally only expressed during the early stages of cell differentiation frozen by neoplastic transformation, playing an important pathophysiological role in the regulatory mechanisms of neoplastic cell survival. In fact, because of its biophysical features, IIR, besides keeping the resting potential within the depolarized values required for unlimited tumor growth, could also appear suitable to afford a selective advantage in an ischemic environment.

Amino Acid Sequence↗
PubMed2002

Evaluation of antidepressant-related behavioral responses in mice lacking the serotonin transporter.

Inhibition of the serotonin transporter (5-HTT) is a principal initial target of many antidepressants. However, the contribution of the 5-HTT to their therapeutic efficacy is incompletely understood. We utilized a targeted gene mutation approach to examine the role of the 5-HTT in the behavioral actions of antidepressants. The 5-HTT mutation was bred onto two separate genetic backgrounds, C57BL/6J and 129S6. On a preliminary screen for gross physical, neurological and behavioral functions, all measures were normal with the exception that 5-HTT -/- mice on the C57BL/6J background showed increased body weight and poor rotarod performance, and 5-HTT -/- mice on the 129S6 background showed reduced neuromuscular strength. On the tail suspension test, 5-HTT -/- mice on the 129S6 background showed a baseline antidepressant-like reduction in immobility. In contrast, the same mice showed increased immobility in the forced swim test, possibly due to compromised neuromuscular strength. 5-HTT -/- mice on the C57BL/6J background showed no baseline antidepressant-related phenotype on either test. The behavioral effects of three antidepressants were tested in 5-HTT mutant mice (C57BL/6J background) in the tail suspension test. The anti-immobility effects of the serotonin reuptake inhibitor, fluoxetine (30 mg/kg), were abolished in 5-HTT -/- mice, confirming that the 5-HTT gene is required for the behavioral effects of fluoxetine. In contrast, 5-HTT-/- mice retained sensitivity to the anti-immobility effects of the norepinephrine reuptake inhibitor, desipramine (20 mg/kg), and the mixed serotonin/norepinephrine reuptake inhibitor, imipramine (25 mg/kg). 5-HTT knockout mice provide a valuable tool for delineating the neuropsychopharmacological actions of antidepressants.

Animals↗
PubMed1995

On the difficulty of making a mutative interpretation.

Beginning with Strachey's formulation of the mutative interpretation as the vehicle of the therapeutic action of psychoanalysis, the author considers what makes a mutative interpretation difficult for the analyst. He concludes that this difficulty stems from a relationship of mutual projective identification between patient and analyst, which produces an atmosphere antagonistic to analysis. By viewing the analytic dyad as a group of two, it is possible to relate this anti-analytic atmosphere to Freud's and Bion's theories of group mentality. The author also concludes that Strachey's 'auxiliary superego' is indistinguishable in practice from the analyst's ego, since it is concerned only with 'real and contemporary' events, and suggests that our understanding of what is specific to the therapeutic action of psychoanalysis would be simplified and improved if we replaced Strachey's terms 'auxiliary superego' and 'mature superego' with 'ego'. A successful mutative interpretation is a victory of ego over superego; this process requires that the analyst free himself from the intellectual deterioration that the fusion of superegos has produced; and this accomplishes one of the purposes of analysis: to help the patient think and feel what is true.

Adult↗
PubMed2005

The gonadotropin-releasing hormone (GnRH)-1 gene, the GnRH receptor gene, and their promoters in patients with idiopathic hypogonadotropic hypogonadism with or without resistance to GnRH action.

The study included 26 patients with idiopathic hypogonadotropic hypogonadism (24 sporadic and 2 familial). The Pro146Ser mutation was identified in the gonadotropin-releasing hormone receptor (GnRHR) gene in two sisters as well as in their mother, and one polymorphism in the GnRH1 gene (the Trp16Ser) was identified in four patients. No mutations in transcription factor-binding sites of their promoters were identified. Three patients (one male and two sisters) were found with resistance to GnRH action. No mutations were identified in the male, whereas in the females the mutation Pro146Ser in the GnRHR was identified in heterozygosity.

Adult↗