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PubMed2001

The ectopic overexpression of a citrus gibberellin 20-oxidase enhances the non-13-hydroxylation pathway of gibberellin biosynthesis and induces an extremely elongated phenotype in tobacco.

Transgenic plants of Nicotiana tabacum overexpressing a gibberellin (GA) 20-oxidase cDNA (CcGA20ox1) from citrus, under the control of the 35S promoter, were taller (up to twice) and had larger inflorescences and longer flower peduncles than those of control plants. Hypocotyls of transgenic seedlings were also longer (up to 4 times), and neither the seedlings nor the growing plants elongated further after application of GA3. Hypocotyl and stem lengths were reduced by application of paclobutrazol, and this inhibition was reversed by exogenous GA3. The ectopic overexpression of CcGA20ox1 enhanced the non-13-hydroxylation pathway of GA biosynthesis leading to GA4, apparently at the expense of the early-13-hydroxylation pathway. The level of GA4 (the active GA from the non-13-hydroxylation pathway) in the shoot of transgenic plants was 3-4 times higher than in control plants, whereas that of GA1, formed via the early-13-hydroxylation pathway (the main GA biosynthesis pathway in tobacco), decreased or was not affected. GA4 applied to the culture medium or to the expanding leaves was found to be at least equally active as GA1 on stimulating hypocotyl and stem elongation of tobacco plants. The results suggest that the tall phenotype of tobacco transgenic plants was due to their higher content of GA4, and that the GA response was saturated by the presence of the transgene.

Journal Article↗
PubMed1993

Interlaminar connections of the superior colliculus in the tree shrew. I. The superficial gray layer.

One of the most persistent problems in the study of the superior colliculus is the relationship between its superficial and deep layers. The superficial tier of layers is considered to be visuosensory in function, whereas the deep tier is multisensory and has premotor functions. This fundamental distinction is the primary basis for the view that a visually triggered shift in the direction of gaze depends on the transfer of information from sensory cells in the superficial tier to premotor cells in the deep tier. The goal of the present experiments was to examine the interlaminar projections of the superficial gray layer in the tree shrew Tupaia belangeri. We used biocytin as the marker for tracing the pathways. The tree shrew was chosen because its large and distinctly laminated superior colliculus facilitates the task of examining connections between the layers. Biocytin was used because of its sensitivity and because it allowed us to place very small injections restricted entirely to the superficial gray layer. The results demonstrated that a prominent pathway originates in the superficial gray layer and terminates in stratum opticum. In comparison, the projection from the superficial gray layer to the layers beneath stratum opticum is extremely sparse. The pathway from the superficial gray layer to stratum opticum has a columnar distribution, extending about 100 microns rostrally and caudally from the center of the injection site. There were no signs of more remote intracollicular connections, nor of patches or bands of terminals. The biocytin injection sites also labeled pathways to nuclei as distant from the superior colliculus as the diencephalon, including the dorsal and ventral lateral geniculate bodies, and the pulvinar. The results suggest that stratum opticum may serve as a link between the superficial gray layer and the deeper layers.

Animals↗
PubMed1992

Characteristics of local electrogram predicting successful transcatheter radiofrequency ablation of left-sided accessory pathways.

OBJECTIVES: The purpose of this study was to analyze and compare the local electrograms recorded at successful and unsuccessful sites of ablation to identify the criteria that may predict successful sites and minimize unnecessary radiofrequency delivery. BACKGROUND: Transcatheter ablation of accessory pathways using radiofrequency energy requires extremely precise localization of an accessory pathway. METHODS: Local electrograms from 50 consecutive patients with left-sided accessory pathways who underwent transcatheter radiofrequency ablation were analyzed. During catheter ablation, localization of accessory pathways was performed in 39 pathways during pre-excited sinus rhythm and in 14 pathways during orthodromic tachycardia. A total of 429 local electrograms at target sites obtained before delivery of radiofrequency current was analyzed. A prospective study was performed in another 20 patients using the criteria derived from the retrospective study. RESULTS: Accessory pathway conduction block was achieved in 36 (92%) of 39 pathways in which mapping was performed during pre-excited sinus rhythm and in 9 (64%) of 14 pathways in which mapping was performed during orthodromic tachycardia (p less than 0.05). When mapping was performed during pre-excited sinus rhythm, a combination of four variables (that is, an accessory pathway potential, stability of local electrograms, atrial activation greater than 1 mV and ventricular activation preceding the onset of the delta wave) showed a 62% probability of success. In contrast, excluding these variables resulted in a 95% probability of failure (noneffective or transiently effective). The prospective study shows that the use of these criteria can significantly reduce the number of current applications. When mapping was performed during orthodromic tachycardia, recording the earliest atrial activation was the most powerful predictor of success. A stable local electrogram with a small notch on the ventricular potential, presumed to be an accessory pathway potential, may add predictive value. CONCLUSIONS: Transcatheter radiofrequency ablation is highly effective in the treatment of patients with left-sided accessory pathways. Specific characteristics of local electrograms can be important predictors of success or failure. Mapping during pre-excited rhythm renders ablation more effective than does mapping during orthodromic tachycardia.

Adolescent↗
PubMed1998

Differential regulation of dopamine release by N-methyl-D-aspartate receptors in rat striatum after partial and extreme lesions of the nigro-striatal pathway.

The participation of N-methyl-d-aspartate (NMDA) receptors on dopamine (DA) efflux in the striatum of anaesthetized rats, which had their DA nigrostriatal pathway previously lesioned with different doses of 6-hydroxydopamine (6-OH-DA), was assessed by in vivo microdialysis methodology. In addition, the in vivo basal DA and dihydroxy-phenyl-acetic acid (DOPAC) effluxes and the effect of local K+-depolarization on DA release were also evaluated in the striatum of these 6-OH-DA treated rats. Lesioned rats were divided in three groups corresponding to animals with 25-75%, 75-95% and >95% of striatum tissue DA depletion, respectively. Striatal DA tissue depletion between 25-75% occurred in parallel with a 30% reduction in DA extracellular levels, with a moderate 10% increase in basal fractional DA efflux, and with no statistical changes in the fractional DA efflux induced by NMDA (500 microM) receptor stimulation by reverse dialysis. Rats with higher DA tissue depletion (between 75-95%) exhibited a 60% reduction in DA extracellular levels in the striatum and this reduction occurred in parallel with a modest rise in basal fractional DA efflux, but with a striking decrease in the NMDA-induced fractional DA efflux. In rats with extreme or >95% of striatal DA tissue depletion, basal fractional DA efflux in the striatum increased quite substantially along with a recovery in the ability of NMDA receptor stimulation to induce fractional DA release. The >95% striatal DA-depleted rats also exhibited a significant decrease in tissue and extracellular DOPAC/DA ratio when compared to sham and partially DA-depleted rats. In contrast to the previous results, fractional DA efflux induced by reverse dialysis with K+ (40 mM) remained the same in the striatum of sham and all groups of DA-tissue depleted rats. The present findings suggest the existence of at least three features associated to the regulation of basal and NMDA-induced extracellular levels of DA in the striatum of rats as a function of striatal tissue DA depletion produced by 6-OH-DA. They also support the view that a differential regulation of basal and NMDA-induced DA extracellular levels occur in partial and extreme DA-depleted striatum after 6-OH-DA treatment. Such findings may have implications as regard to the participation of the NMDA receptor in the compensatory mechanisms associated to the progress of Parkinson's disease, as well as in the therapeutic treatment of this neurological disorder.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2001

Sex from W to Z: evolution of vertebrate sex chromosomes and sex determining genes.

Sex determination in major vertebrate groups appears to be very variable, including systems of male heterogamety, female heterogamety and a variety of genetic and environmental sex determining systems. Yet comparative studies of sex chromosomes and sex determining genes now suggest that these differences are more apparent than real. The sex chromosomes of even widely divergent groups now appear to have changed very little over the last 300+ million years, and even independently derived sex chromosomes seem to have followed the same set of evolutionary rules. The sex determining pathway seems to be extremely conserved, although the control of the genes in this pathway is vested in different elements. We present a scenario for the independent evolution of XY male heterogamety in mammals and ZW female heterogamety in birds and some reptiles. We suggest that sex determining genes can be made redundant, and replaced by control at another step of a conserved sex determining pathway, and how choice of a gene as a sex switch has led to the evolution of new sex chromosome systems. J. Exp. Zool. 290:449-462, 2001.

Animals↗
PubMed2004

Design of a directed molecular network.

An ability to rationally design complex networks from the bottom up can offer valuable quantitative model systems for use in gaining a deeper appreciation for the principles governing the self-organization and functional characteristics of complex systems. We report herein the de novo design, graph prediction, experimental analysis, and characterization of simple self-organized, nonlinear molecular networks. Our approach makes use of the sequence-dependent auto- and cross-catalytic functional characteristics of template-directed peptide fragment condensation reactions in neutral aqueous solutions. Starting with an array of 81 sequence similar 32-residue coiled-coil peptides, we estimated the relative stability difference between all plausible A(2)B-type coiled-coil ensembles and used this information to predict the auto- and cross-catalysis pathways and the resulting plausible network motif and connectivities. Similar to most complex systems, the generated graph displays clustered nodes with an overall hierarchical architecture. To test the validity of the design principles used, nine nodes composing a main segment of the graph were experimentally analyzed for their capacity in establishing the predicted network connectivity. The resulting self-organized chemical network is shown to display 25 directed edges in good agreement with the graph analysis estimations. Moreover, we show that by varying the system parameters (presence or absence of certain substrates or templates), its operating network motif can be altered, even to the extremes of turning pathways on or off. We suggest that this approach can be expanded for the construction of large-scale networks, offering a means to study and to understand better the emergent, collective behaviors of networks.

Amino Acid Sequence↗
PubMed1989

13C-NMR study of acetate assimilation in Thermoproteus neutrophilus.

Acetate assimilation into amino acids and the functioning of central biosynthetic pathways in the extremely thermophilic anaerobic archaebacterium Thermoproteus neutrophilus was investigated using 13C NMR as the method for determination of the labelling patterns. Acetate was assimilated via reductive carboxylation of acetyl-CoA to pyruvate and pyruvate conversion to phosphoenolpyruvate which was further carboxylated to oxaloacetate. 2-Oxoglutarate was mainly formed via citrate. However, the labelling patterns of glutamic acid and alanine were in agreement with the concurrent synthesis of about 15% 2-oxoglutarate and 5% pyruvate through the reductive citric acid cycle. A scrambling phenomenon occurring in aspartate and all amino acids derived through oxaloacetate was observed. The labelling patterns of amino acids were in agreement with their standard biosynthetic pathways, with two remarkable exceptions: isoleucine was synthesized via the citramalate pathway and lysine was synthesized via the 2-aminoadipate pathway which has previously been reported only in eukaryotic microorganisms.

Acetates↗
PubMed2006

"Translating" tumor hypoxia: unfolded protein response (UPR)-dependent and UPR-independent pathways.

Poor oxygenation (hypoxia) is present in the majority of human tumors and is associated with poor prognosis due to the protection it affords to radiotherapy and chemotherapy. Hypoxia also elicits multiple cellular response pathways that alter gene expression and affect tumor progression, including two recently identified separate pathways that strongly suppress the rates of mRNA translation during hypoxia. The first pathway is activated extremely rapidly and is mediated by phosphorylation and inhibition of the eukaryotic initiation factor 2alpha. Phosphorylation of this factor occurs as part of a coordinated endoplasmic reticulum stress response program known as the unfolded protein response and activation of this program is required for hypoxic cell survival and tumor growth. Translation during hypoxia is also inhibited through the inactivation of a second eukaryotic initiation complex, eukaryotic initiation factor 4F. At least part of this inhibition is mediated through a Redd1 and tuberous sclerosis complex 1/2-dependent inhibition of the mammalian target of rapamycin kinase. Inhibition of mRNA translation is hypothesized to affect the cellular tolerance to hypoxia in part by promoting energy homeostasis. However, regulation of translation also results in a specific increase in the synthesis of a subset of hypoxia-induced proteins. Consequently, both arms of translational control during hypoxia influence gene expression and phenotype. These hypoxic response pathways show differential activation requirements that are dependent on the level of oxygenation and duration of hypoxia and are themselves highly dynamic. Thus, the severity and duration of hypoxia can lead to different biological and therapeutic consequences.

Cell Hypoxia↗
PubMedDate not supplied

Partial 17, 20-desmolase and 17 alpha-hydroxylase deficiencies in a 16-year-old boy.

Thirteen plasma steroids as well as ACTH, LH and FSH were measured by specific RIAs under basal and dynamic conditions in a 16-year-old boy (normal external genitalia, 46, XY karyotype) who presented slowness and unachievement of pubertal development. On the delta 4-pathway: basal levels of testosterone and dihydrotestosterone were low- with a normal ratio-, delta 4-androstenedione and 11 beta-hydroxyandrostenedione were in the low normal range. Meanwhile, 17 alpha-hydroxyprogesterone and progesterone levels were markedly elevated. On the delta 5-pathway: dehydroepiandrosterone was extremely low while 17 alpha-hydroxypregnenolone and pregnenolone were almost normal; dehydroepiandrosterone sulfate was subnormal while pregnenolone sulfate was normal. Cortisol, aldosterone were normal while ACTH was moderately increased. Basal and responsive levels of LH and FSH were markedly increased. ACTH stimulation induced a subnormal rise of cortisol and 11 beta-hydroxyandrostenedione, a low or absent rise of dehydroepiandrosterone, 17 alpha-hydroxypregnenolone, androstenedione and 17 alpha-hydroxyprogesterone contrasting with a marked rise of pregnenolone and progesterone. After hCG stimulation, responses were low for testosterone, extremely high for 17 alpha-hydroxyprogesterone with a normalisation of the 17 alpha-hydroxyprogesterone/progesterone ratio. Fluoxymesterone dramatically reduced the pathologically high basal levels of progesterone and 17 alpha hydroxyprogesterone. Dexamethasone induced only a minute decrease in the delta 4-progestagens, a marked decrease in pregnenolone, with a more than 80% reduction of 17 alpha- hydroxypregnenolone, dehydroepiandrosterone, dehydroepiandrosterone sulfate and androstenedione. These data suggest a defect involving the cytochrome P450 common to both 17 alpha-hydroxylase and 17, 20-desmolase activities.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1983

Anti-idiotype antibody-dependent cell-mediated cytotoxicity (ADCC) against idiotype-bearing cells.

The present report demonstrates that cells expressing idiotypic determinants on their surfaces can be specifically destroyed by anti-idiotypic antibodies acting as inducers of antibody-dependent cell-mediated cytotoxicity. Lysis of surface-idiotype-positive hybridoma cells was effected by mouse spleen cells, mouse peritoneal cells, or human blood mononuclear cells, in the presence of anti-idiotypic antibodies. In order for lysis to occur, the simultaneous presence of Fc receptor-bearing cytotoxic cells and anti-idiotypic antibodies was required. Specificity of lysis was conferred by the anti-idiotypic antibody. Hybridoma cells expressing a different idiotype could not be lysed. Anti-idiotypic antibody-dependent cell-mediated cytotoxicity against 51Cr-labeled cells expressing a particular idiotype could be induced by the specific anti-idiotypic antibodies and inhibited by unlabeled idiotype-positive cells or by idiotype in a soluble form. Cytotoxicity could not be inhibited by the presence of bystander cells or monoclonal antibodies expressing a different idiotype. It is proposed that ADCC lysis of idiotype-positive cells has important implications for understanding the regulation of immune responses by an idiotype-anti-idiotype network. This cytolytic pathway provides an extremely specific and effective mode of control of idiotype-positive cells by anti-idiotype antibody. Previous observations that an intact Fc fragment was necessary for anti-idiotype antibodies to exert suppressive effects in vivo further support this hypothesis.

Animals↗
PubMed2006

Effects of treadmill exercise on transcranial magnetic stimulation-induced excitability to quadriceps after stroke.

OBJECTIVE: To determine characteristics of transcranial magnetic stimulation (TMS)-induced measures of central motor excitability to the paretic and nonparetic quadriceps muscles of chronic hemiparetic stroke patients in the context of a short-term, submaximal bout treadmill exercise. DESIGN: Cross-sectional. SETTING: Motor control and gait biomechanics laboratory. PARTICIPANTS: Convenience sample of 11 patients including cohorts of treadmill untrained (n=8) and trained (n=3) stroke patients with chronic hemiparetic gait. INTERVENTION: Short-term submaximal treadmill exercise. MAIN OUTCOME MEASURES: Thresholds, amplitudes and latencies of TMS-induced motor evoked potentials at vastus medialis in paretic and nonparetic lower extremities. RESULTS: Baseline characteristics of the motor evoked potentials (MEPs) show significantly higher motor thresholds, longer latencies, and reduced amplitudes on the paretic side. In cross-sectional comparisons a group of treadmill-trained patients had greater paretic MEP amplitude changes after treadmill exercise versus paretic MEP responses from a group of untrained patients. CONCLUSIONS: These results indicate that treadmill training for 3 months or more may alter responsiveness of the lower-extremity central motor pathways to a short-term treadmill stimulus.

Aged↗
PubMed2005

Up-regulation of site-specific remodeling without accumulation of microcracking and loss of osteocytes.

Functional adaptation of bone normally protects the skeleton from fracture during daily activity. Accumulation of microcracking and loss of osteocytes have been implicated in the regulation and initiation of targeted (reparative) remodeling of bone and, in certain situations, the development of fatigue or stress fracture. We performed a histologic study of the dorsal cortex of the mid-diaphysis of the third metacarpal (Mc-III) bone of Thoroughbred racehorses after bones were bulk-stained in basic fuchsin and transverse calcified sections were prepared. The Thoroughbred racehorse is an extreme athlete whose Mc-III bone experiences particularly high cyclic strains during training and racing. A group of non-athletic horses was also included in the experiment. The following variables were quantified: activation frequency (Ac.f); bone formation rate (BFR); resorption space density (Rs.N/T.Ar); microcrack density (Cr.Dn); microcrack mean length (Cr.Le); microcrack surface density (Cr.S.Dn); osteocyte density (Ot.N/T.Ar; Ot.N/B.Ar); and bone volume fraction (B.Ar/T.Ar). Ac.f and BFR were estimated using a mathematical algorithm. Using confocal microscopy, bones were examined for fine microcracks, diffuse matrix injury, and disruption of the osteocyte syncytium. Low values for Cr.Dn (#/mm2) were found in both groups (0.022+/-0.008 and 0.013+/-0.006 for racing Thoroughbreds and non-athletic horses, respectively). There was no significant relationship between Cr.Dn and Ot.N/T.Ar; Ot.N/B.Ar, B.Ar/T.Ar, and Ot.N/T.Ar; Ot.N/B.Ar, and remodeling (Ac.f, Rs.N/T.Ar) and Ot.N/T.Ar; Ot.N/B.Ar. Intense remodeling of the Mc-III dorsal cortex was found in the racing Thoroughbreds (Ac.f 12.8+/-7.4 #/mm2/year; BFR 31.5+/-15.6%; Rs.N/T.Ar 0.19+/-0.09 #/mm2) and was significantly increased compared with non-athletic horses. Overall, remodeling was weakly correlated with Cr.Dn (r2=0.15, P<0.05). Subtle matrix injury, not detectable by bright-field microscopy, was particularly evident adjacent to resorption spaces in Thoroughbred bone. In non-athletic horses, disruption of the dendritic cell processes of osteocytes associated with cement lines and interstitial fragments was more evident. Taken together, these findings suggest that site-specific (targeted) induction of remodeling during functional adaptation of bone in a high-strain skeletal site is not dependent on accumulation of microcracking or loss of osteocytes. We hypothesize that athleticism can directly influence bone turnover in this extreme athlete through pathways that do not involve classical linear microcracks.

Age Factors↗
PubMed2005

Trypanosoma brucei: TbRAB4 regulates membrane recycling and expression of surface proteins in procyclic forms.

TbRAB4 is the Trypanosoma brucei orthologue of the small GTPase Rab4, which is implicated in the control of early endocytosis and recycling processes. TbRAB4 is expressed constitutively in the procyclic and bloodstream stages suggesting an important function throughout the trypanosome life-cycle. Previous work from our laboratory has shown TbRAB4 to be essential in the bloodstream form. Induction of double-stranded TbRAB4 RNA expression leads to a specific reduction in TbRAB4 protein levels and inhibition of growth in procyclic form T. brucei, with alterations in uptake and recycling as measured with the fluorophore FM4-64. Trypanosomes overexpressing GTP-locked TbRAB4(QL) mutants exhibit significant perturbations of endocytic and recycling pathways as well as disruption of surface expression of GPI-anchored proteins. Most significantly, both the endogenous GPI-anchored procyclins and an ectopically expressed GPI-anchored protein, the variant surface glycoprotein, are relocated from the surface to internal sites in TbRAB4 mutant cells. These data indicate that TbRAB4 is important in maintenance of normal surface expression of lipid-anchored proteins, and implicate recycling pathways as factors for modulation of surface protein expression in the procyclic trypanosome. The conservation of function of Rab4 throughout eukaryotic evolution demonstrated here indicates that the Rab4-mediated trafficking pathway is an extremely ancient component of the endocytic system.

Animals↗
PubMed2002

Nuclear inositol lipid signaling and its potential involvement in malignant transformation.

Growth, differentiation, and apoptosis of eukaryotic cells are mediated by extremely complex signaling pathways and a high degree of coordination is required for regulating cell proliferation. In multicellular organisms homeostasis is achieved through signal transduction events. If these homeostatic mechanisms are interrupted, a disease, such as cancer, may ensue. Lipid second messengers, particularly those derived from polyphosphoinositide cycle, play a pivotal role in several cell signaling networks. Evidence accumulated over the past 15 years has highlighted the presence of an autonomous nuclear inositol lipid metabolism, and suggests that lipid signaling molecules are important components of signaling pathways operating within the nucleus. Recent findings are starting to elucidate how the nuclear phosphoinositide cycle is regulated and what down-stream molecules are targeted through this cycle. In this review, we shall summarize the most updated data about inositol lipid-dependent nuclear signaling pathways that might have a relevance for the development of cancer. In the near future, this knowledge might also prove to have relevance for the diagnosis and treatment of the neoplastic disease.

Animals↗
PubMed1999

Channeling of carbamoyl phosphate to the pyrimidine and arginine biosynthetic pathways in the deep sea hyperthermophilic archaeon Pyrococcus abyssi.

The kinetics of the coupled reactions between carbamoyl-phosphate synthetase (CPSase) and both aspartate transcarbamoylase (ATCase) and ornithine transcarbamoylase (OTCase) from the deep sea hyperthermophilic archaeon Pyrococcus abyssi demonstrate the existence of carbamoyl phosphate channeling in both the pyrimidine and arginine biosynthetic pathways. Isotopic dilution experiments and coupled reaction kinetics analyzed within the context of the formalism proposed by Ovádi et al. (Ovádi, J., Tompa, P., Vertessy, B., Orosz, F., Keleti, T., and Welch, G. R. (1989) Biochem. J. 257, 187-190) are consistent with a partial channeling of the intermediate at 37 degrees C, but channeling efficiency increases dramatically at elevated temperatures. There is no preferential partitioning of carbamoyl phosphate between the arginine and pyrimidine biosynthetic pathways. Gel filtration chromatography at high and low temperature and in the presence and absence of substrates did not reveal stable complexes between P. abyssi CPSase and either ATCase or OTCase. Thus, channeling must occur during the dynamic association of coupled enzymes pairs. The interaction of CPSase-ATCase was further demonstrated by the unexpectedly weak inhibition of the coupled reaction by the bisubstrate analog, N-(phosphonacetyl)-L-aspartate (PALA). The anomalous effect of PALA suggests that, in the coupled reaction, the effective concentration of carbamoyl phosphate in the vicinity of the ATCase active site is 96-fold higher than the concentration in the bulk phase. Channeling probably plays an essential role in protecting this very unstable intermediate of metabolic pathways performing at extreme temperatures.

Adaptation, Biological↗
PubMed2004

Complete genome sequence of the apicomplexan, Cryptosporidium parvum.

The apicomplexan Cryptosporidium parvum is an intestinal parasite that affects healthy humans and animals, and causes an unrelenting infection in immunocompromised individuals such as AIDS patients. We report the complete genome sequence of C. parvum, type II isolate. Genome analysis identifies extremely streamlined metabolic pathways and a reliance on the host for nutrients. In contrast to Plasmodium and Toxoplasma, the parasite lacks an apicoplast and its genome, and possesses a degenerate mitochondrion that has lost its genome. Several novel classes of cell-surface and secreted proteins with a potential role in host interactions and pathogenesis were also detected. Elucidation of the core metabolism, including enzymes with high similarities to bacterial and plant counterparts, opens new avenues for drug development.

Animals↗
PubMed2001

RNA localization meets wingless signaling.

In many tissues in many organisms, messenger RNA (mRNA) is not randomly distributed throughout a cell, but is targeted and accumulated in specific subcellular locations. Signal transduction pathways can be extremely sensitive to gradients of signaling proteins and represent a cellular phenomenon where RNA localization may be important. Manseau discusses how targeting of the RNA for a secreted ligand, Wingless (Wg), is important in promoting proper Wg signaling in early Drosophila embryos and the mechanism for achieving this subcellular targeting. The possible mechanistic models for how restricted wg mRNA distribution influences Wg signaling are also detailed.

Animals↗
PubMed1994

The Escherichia coli AlkB protein protects human cells against alkylation-induced toxicity.

Escherichia coli can ameliorate the toxic effects of alkylating agents either by preventing DNA alkylation or by repairing DNA alkylation damage. The alkylation-sensitive phenotype of E. coli alkB mutants marks the alkB pathway as an extremely effective defense mechanism against the cytotoxic effects of the SN2, but not the SN1, alkylating agents. Although it is clear that AlkB helps cells to better handle alkylated DNA, no DNA alkylation repair function could be assigned to the purified AlkB protein, suggesting that AlkB either acts as part of a complex or acts to regulate the expression of other genes whose products are directly responsible for alkylation resistance. However, here we present evidence that the provision of alkylation resistance is an intrinsic function of the AlkB protein per se. We expressed the E. coli AlkB protein in two human cell lines and found that it confers the same characteristic alkylation-resistant phenotype in this foreign environment as it does in E. coli. AlkB expression rendered human cells extremely resistant to cell killing by the SN2 but not the SN1 alkylating agents but did not affect the ability of dimethyl sulfate (an SN2 agent) to alkylate the genome. We infer that SN2 agents produce a class of DNA damage that is not efficiently produced by SN1 agents and that AlkB somehow prevents this damage from killing the cell.

AlkB Homolog 1, Histone H2a Dioxygenase↗