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1.
Artículo en Inglés | MEDLINE | ID: mdl-30670430

RESUMEN

DS86760016 is a new leucyl-tRNA-synthetase inhibitor at the preclinical development stage. DS86760016 showed potent activity against extended-spectrum multidrug-resistant Pseudomonas aeruginosa isolated from clinical samples and in vitro biofilms. In a murine catheter-associated urinary tract infection model, DS86760016 treatment resulted in significant eradication of P. aeruginosa from the kidney, bladder, and catheter without developing drug resistance. Our data suggest that DS86760016 has the potential to act as a new drug for the treatment of Pseudomonas infections.


Asunto(s)
Antibacterianos/farmacología , Compuestos de Boro/farmacología , Infecciones Relacionadas con Catéteres/tratamiento farmacológico , Dioxoles/farmacología , Leucina-ARNt Ligasa/antagonistas & inhibidores , Metilaminas/farmacología , Infecciones por Pseudomonas/tratamiento farmacológico , Pseudomonas aeruginosa/efectos de los fármacos , Infecciones Urinarias/tratamiento farmacológico , Animales , Antibacterianos/farmacocinética , Biopelículas/crecimiento & desarrollo , Compuestos de Boro/farmacocinética , Infecciones Relacionadas con Catéteres/microbiología , Dioxoles/farmacocinética , Modelos Animales de Enfermedad , Farmacorresistencia Bacteriana Múltiple , Femenino , Humanos , Metilaminas/farmacocinética , Ratones , Pruebas de Sensibilidad Microbiana , Infecciones por Pseudomonas/microbiología , Infecciones Urinarias/microbiología
2.
Artículo en Inglés | MEDLINE | ID: mdl-29437618

RESUMEN

The emergence of multidrug-resistant (MDR) Gram-negative bacilli is a major concern in the treatment of nosocomial infections. Antibacterial agents with novel modes of action can be useful, as these pathogens have become resistant to almost all existing standard-of-care agents. GSK2251052, a leucyl-tRNA synthetase inhibitor, has a novel mode of action against Gram-negative bacteria. However, the phase 2 studies with this drug were terminated due to microbiological failures based on the rapid emergence of drug resistance during the treatment of complicated urinary tract infections. DS86760016 is a novel leucyl-tRNA synthetase inhibitor active against MDR Gram-negative bacteria, such as Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa, with an improved pharmacokinetic profile. DS86760016 showed lower plasma clearance, longer plasma half-life, and higher renal excretion than GSK2251052 did in mice, rats, monkeys and dogs. DS86760016 also showed lower mutant prevention concentrations against P. aeruginosa than did GSK2251052. No resistant bacteria were observed in murine urinary tract infection models at a dose that maintained urinary concentrations above the mutant prevention concentration. DS86760016 also showed a lower risk of resistance development than did GSK2251052 in comparative in vivo studies with murine urinary tract infection models. These results suggest that DS86760016 has potential as a new drug for the treatment of MDR Gram-negative bacterial infections, with a lower risk of drug resistance development than that of GSK2251052.


Asunto(s)
Antibacterianos/uso terapéutico , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Gramnegativas/patogenicidad , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Leucina-ARNt Ligasa/antagonistas & inhibidores , Animales , Compuestos de Boro/uso terapéutico , Farmacorresistencia Bacteriana Múltiple/genética , Femenino , Klebsiella pneumoniae/efectos de los fármacos , Klebsiella pneumoniae/enzimología , Klebsiella pneumoniae/patogenicidad , Leucina-ARNt Ligasa/metabolismo , Macaca fascicularis , Masculino , Ratones , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/enzimología , Pseudomonas aeruginosa/patogenicidad , Infecciones Urinarias/tratamiento farmacológico , Infecciones Urinarias/microbiología
3.
Bioorg Med Chem Lett ; 27(15): 3454-3459, 2017 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-28587823

RESUMEN

A non-diaryl quinoline scaffold 6,7-dihydropyrazolo[1,5-a]pyrazin-4-one was identified by screening of diverse set of compounds against M. smegmatis ATP synthase. Herein, we disclose our efforts to develop the structure activity relationship against Mycobacterium tuberculosis (Mtb.H37Rv strain) around the identified hit 1. A scaffold hopping approach was used to identify compounds 14a, 14b and 24a with improved activity against MTb.H37Rv.


Asunto(s)
Complejos de ATP Sintetasa/antagonistas & inhibidores , Antituberculosos/química , Antituberculosos/farmacología , Mycobacterium tuberculosis/enzimología , Quinolinas/química , Quinolinas/farmacología , Complejos de ATP Sintetasa/metabolismo , Antituberculosos/síntesis química , Diseño de Fármacos , Humanos , Mycobacterium tuberculosis/efectos de los fármacos , Pirazinas/síntesis química , Pirazinas/química , Pirazinas/farmacología , Quinolinas/síntesis química , Relación Estructura-Actividad , Tuberculosis/tratamiento farmacológico , Tuberculosis/microbiología
4.
Antimicrob Agents Chemother ; 58(8): 4283-9, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-24550341

RESUMEN

We present here the novel ketolide RBx 14255, a semisynthetic macrolide derivative obtained by the derivatization of clarithromycin, for its in vitro and in vivo activities against sensitive and macrolide-resistant Streptococcus pneumoniae. RBx 14255 showed excellent in vitro activity against macrolide-resistant S. pneumoniae, including an in-house-generated telithromycin-resistant strain (S. pneumoniae 3390 NDDR). RBx 14255 also showed potent protein synthesis inhibition against telithromycin-resistant S. pneumoniae 3390 NDDR. The binding affinity of RBx 14255 toward ribosomes was found to be more than that for other tested drugs. The in vivo efficacy of RBx 14255 was determined in murine pulmonary infection induced by intranasal inoculation of S. pneumoniae ATCC 6303 and systemic infection with S. pneumoniae 3390 NDDR strains. The 50% effective dose (ED50) of RBx 14255 against S. pneumoniae ATCC 6303 in a murine pulmonary infection model was 3.12 mg/kg of body weight. In addition, RBx 14255 resulted in 100% survival of mice with systemic infection caused by macrolide-resistant S. pneumoniae 3390 NDDR at 100 mg/kg four times daily (QID) and at 50 mg/kg QID. RBx 14255 showed favorable pharmacokinetic properties that were comparable to those of telithromycin.


Asunto(s)
Antibacterianos/farmacología , Cetólidos/farmacología , Neumonía Bacteriana/tratamiento farmacológico , Inhibidores de la Síntesis de la Proteína/farmacología , Sepsis/tratamiento farmacológico , Streptococcus pneumoniae/efectos de los fármacos , Animales , Antibacterianos/síntesis química , Antibacterianos/farmacocinética , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Farmacorresistencia Bacteriana , Cetólidos/síntesis química , Cetólidos/farmacocinética , Masculino , Ratones , Pruebas de Sensibilidad Microbiana , Neumonía Bacteriana/microbiología , Neumonía Bacteriana/mortalidad , Neumonía Bacteriana/patología , Inhibidores de la Síntesis de la Proteína/síntesis química , Inhibidores de la Síntesis de la Proteína/farmacocinética , Ribosomas/efectos de los fármacos , Ribosomas/metabolismo , Sepsis/microbiología , Sepsis/mortalidad , Sepsis/patología , Streptococcus pneumoniae/patogenicidad , Streptococcus pneumoniae/fisiología , Análisis de Supervivencia
5.
Antimicrob Agents Chemother ; 53(4): 1427-33, 2009 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-19075051

RESUMEN

Oxazolidinones are known to inhibit protein biosynthesis and act against a wide spectrum of gram-positive bacteria. A new investigational oxazolidinone, ranbezolid, inhibited bacterial protein synthesis in Staphylococcus aureus and Staphylococcus epidermidis. In S. epidermidis, ranbezolid showed inhibition of cell wall and lipid synthesis and a dose-dependent effect on membrane integrity. A kill-kinetics study showed that ranbezolid was bactericidal against S. epidermidis. In vitro translation of the luciferase gene done using bacterial and mammalian ribosomes indicated that ranbezolid specifically inhibited the bacterial ribosome. Molecular modeling studies revealed that both linezolid and ranbezolid fit in similar manners the active site of ribosomes, with total scores, i.e., theoretical binding affinities after consensus, of 5.2 and 6.9, respectively. The nitrofuran ring in ranbezolid is extended toward C2507, G2583, and U2584, and the nitro group forms a hydrogen bond from the base of G2583. The interaction of ranbezolid with the bacterial ribosomes clearly helps to elucidate its potent activity against the target pathogen.


Asunto(s)
Antibacterianos/farmacología , Furanos/farmacología , Oxazoles/farmacología , Inhibidores de la Síntesis de la Proteína/farmacología , Ribosomas/efectos de los fármacos , Staphylococcus aureus/efectos de los fármacos , Staphylococcus epidermidis/efectos de los fármacos , Acetamidas/farmacología , Permeabilidad de la Membrana Celular/efectos de los fármacos , Linezolid , Oxazolidinonas/farmacología , Biosíntesis de Proteínas/efectos de los fármacos , Ribosomas/metabolismo , Transcripción Genética/efectos de los fármacos
6.
FEMS Yeast Res ; 8(5): 676-84, 2008 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-18616605

RESUMEN

Several components of the glucose induction pathway, namely the Snf3p glucose sensor and the Rgt1p and Mth1p transcription factors, were shown to be involved in inhibition of sporulation by glucose. The glucose sensors had only a minor role in regulating transcript levels of the two key regulators of meiotic initiation, the Ime1p transcription factor and the Ime2p kinase, but a major role in regulating Ime2p stability. Interestingly, Rgt1p was involved in glucose inhibition of spore formation but not inhibition of Ime2p stability. Thus, the glucose induction pathway may regulate meiosis through both RGT1-dependent and RGT1-independent pathways.


Asunto(s)
Proteínas de Ciclo Celular/metabolismo , Glucosa/metabolismo , Meiosis , Proteínas Quinasas/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/fisiología , Proteínas de Ciclo Celular/genética , Recuento de Colonia Microbiana , Proteínas de Unión al ADN , Perfilación de la Expresión Génica , Péptidos y Proteínas de Señalización Intracelular , Proteínas de Transporte de Monosacáridos/genética , Proteínas de Transporte de Monosacáridos/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas Quinasas/genética , Proteínas Serina-Treonina Quinasas , Estabilidad del ARN , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Esporas Fúngicas/fisiología , Transactivadores/genética , Transactivadores/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo
7.
Cancer Lett ; 259(1): 1-15, 2008 Jan 18.
Artículo en Inglés | MEDLINE | ID: mdl-18053638

RESUMEN

Enzymes of the cytochrome P450 (CYP) superfamily are the major determinants of half-life and execute pharmacological effects of many therapeutic drugs. In new drug discovery research, recombinant (human) CYPs are also used for identifying active or inactive metabolites that could lead to increased potency or toxicity of a molecule. In addition, CYP inhibition by anticancer drugs might lead to adverse drug reactions, multiple-drug resistance, and drug-drug interactions. During the discovery and pre-clinical evaluation of a New Chemical Entity (NCE), large amounts of purified recombinant CYPs are required for studying metabolism and pharmacokinetic parameters. Therefore, present research efforts are focused to over-express these human CYPs in bacteria, yeast, insect and mammalian cells, followed by their purification on an industrial scale to facilitate identification of novel anticancer drugs. This review summarizes the merits and limitations of these expression systems for an optimized production of individual CYP isoforms, and their usefulness in the discovery and development of target-based, safe and efficacious NCEs for the treatment of cancer.


Asunto(s)
Antineoplásicos/farmacología , Inhibidores Enzimáticos del Citocromo P-450 , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Biotransformación , Clonación Molecular , Sistema Enzimático del Citocromo P-450/genética , Sistema Enzimático del Citocromo P-450/metabolismo , Evaluación Preclínica de Medicamentos , Interacciones Farmacológicas , Resistencia a Antineoplásicos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Humanos , Isoenzimas/antagonistas & inhibidores , Isoenzimas/metabolismo , Farmacogenética , Proteínas Recombinantes/antagonistas & inhibidores , Proteínas Recombinantes/metabolismo , Reproducibilidad de los Resultados
8.
Emerg Infect Dis ; 13(10): 1614-6, 2007 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-18258023

RESUMEN

Decreased susceptibility of Neisseria meningitidis isolates to ciprofloxacin emerged from an outbreak in Delhi, India. Results of antimicrobial susceptibility testing of the meningococcal isolates to ciprofloxacin and further sequencing of DNA gyrase A quinolone-resistance-determining region confirmed the emergence of ciprofloxacin resistance in the outbreak.


Asunto(s)
Brotes de Enfermedades , Farmacorresistencia Bacteriana Múltiple , Infecciones Meningocócicas/epidemiología , Neisseria meningitidis Serogrupo A/efectos de los fármacos , Ciprofloxacina/farmacología , Humanos , India/epidemiología , Infecciones Meningocócicas/tratamiento farmacológico , Pruebas de Sensibilidad Microbiana , Neisseria meningitidis Serogrupo A/clasificación , Neisseria meningitidis Serogrupo A/genética , Serotipificación
9.
Int J Antimicrob Agents ; 27(3): 201-11, 2006 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-16417988

RESUMEN

Vancomycin has been the drug of choice for 30 years for the treatment of methicillin-resistant Staphylococcus aureus (MRSA). Emergence of decreased vancomycin susceptibility in MRSA strains presents a significant clinical problem with few therapeutic options. This study was performed to generate and characterise S. aureus strains with reduced susceptibility to vancomycin. Eighteen S. aureus strains were subjected to serial passaging on vancomycin to generate vancomycin intermediate resistant S. aureus (VISA) strains. Minimum inhibitory concentration (MIC) determination was performed for the parent and the passaged cultures with 13 different antibiotics. The strains were tested by the following five methods: simplified population analysis; CDC method; modified vancomycin agar screen; population analysis profile (PAP); and modified population analysis (PAP-area under the curve (AUC) ratio). Phenotypic changes such as doubling time, synergy with beta-lactam antibiotics and effect on norA efflux pumps were also studied for these strains. The result indicated that 8 VISA mutants (vancomycin MICs, 8-16 microg/mL) were generated in vitro from the 18 S. aureus strains. The CDC and modified agar methods proved to be the most sensitive and specific methods for detection of VISA strains. The PAP for all the VISA strains ranged from 12 microg/mL to > 16 microg/mL, with a PAP-AUC ratio of > 1.3. All mutants showed increased doubling time compared with their parent isolate. Synergism of the vancomycin and beta-lactam combinations was observed for all methicillin-resistant mutants. Upon acquisition of vancomycin resistance, a few mutants showed decreased oxacillin resistance. Two VISA strains were chosen for molecular characterisation of the mecA gene and one mutant showed genotypic changes with deletion of mecA. Loss of norA efflux pumps leading to fluoroquinolone sensitivity was also observed in four mutants.


Asunto(s)
Staphylococcus aureus/efectos de los fármacos , Vancomicina/farmacología , Laboratorios , Pruebas de Sensibilidad Microbiana , Staphylococcus aureus/crecimiento & desarrollo , Resistencia a la Vancomicina
10.
Mol Cell Biol ; 25(1): 440-50, 2005 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-15601864

RESUMEN

In the budding yeast Saccharomyces cerevisiae, the cell division cycle and sporulation are mutually exclusive cell fates; glucose, which stimulates the cell division cycle, is a potent inhibitor of sporulation. Addition of moderate concentrations of glucose (0.5%) to sporulation medium did not inhibit transcription of two key activators of sporulation, IME1 and IME2, but did increase levels of Sic1p, a cyclin-dependent kinase inhibitor, resulting in a block to meiotic DNA replication. The effects of glucose on Sic1p levels and DNA replication required Grr1p, a component of the SCF(Grr1p) ubiquitin ligase. Sic1p is negatively regulated by Ime2p kinase, and several observations indicate that glucose inhibits meiotic DNA replication through SCF(Grr1p)-mediated destruction of this kinase. First, Ime2p was destabilized in the presence of glucose, and this turnover required Grr1p, a second component of SCF(Grr1p), Cdc53p, and an SCF(Grr1p)-associated E2 enzyme, Cdc34p. Second, Ime2p-ubiquitin conjugates were detected under conditions of rapid Ime2p turnover, and conjugation of Ime2p to ubiquitin required GRR1. Third, a mutant form of Ime2p (Ime2(DeltaPEST)), in which a putative Grr1p-interacting sequence was deleted, was more stable than wild-type Ime2p. Finally, expression of the IME2(DeltaPEST) allele bypassed the block to meiotic DNA replication caused by 0.5% glucose. In addition, Grr1p is required for later events in sporulation independently of its role in Ime2p turnover.


Asunto(s)
Proteínas de Ciclo Celular/metabolismo , Replicación del ADN , Glucosa/metabolismo , Meiosis , Proteínas Quinasas/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/fisiología , Ubiquitina-Proteína Ligasas/fisiología , Alelos , Ciclosoma-Complejo Promotor de la Anafase , Ciclo Celular , Núcleo Celular/metabolismo , Proliferación Celular , Separación Celular , Clonación Molecular , Medios de Cultivo/metabolismo , Medios de Cultivo/farmacología , Proteínas Inhibidoras de las Quinasas Dependientes de la Ciclina , ADN/metabolismo , Proteínas F-Box , Citometría de Flujo , Regulación Fúngica de la Expresión Génica , Péptidos y Proteínas de Señalización Intracelular , Mutación , Plásmidos/metabolismo , Unión Proteica , Proteínas Serina-Treonina Quinasas , ARN/metabolismo , Recombinación Genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Factores de Tiempo , Transcripción Genética , Ubiquitina/metabolismo , Complejos de Ubiquitina-Proteína Ligasa/metabolismo , Ubiquitina-Proteína Ligasas/genética
11.
Cell Cycle ; 3(11): 1433-9, 2004 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-15611626

RESUMEN

In the yeast Saccharomyces cerevisiae, mitotic cell cycle progression depends upon the G(1)-phase cyclin-dependent kinase Cln-Cdc28 and cell growth to a minimum cell size. In contrast, Cln-Cdc28 inhibits entry into meiosis, and a cell growth requirement for sporulation has not been established. Here, we report that entry into meiosis also depends upon cell growth. Moreover, sporulation and cell growth rates were proportional to cell size; large cells grew rapidly and sporulated sooner while smaller cells grew slowly and sporulated later. In addition, Cln2 protein levels were higher in smaller cells suggesting that Cln-Cdc28 activity represses meiosis in smaller cells by preventing cell growth. In support of this hypothesis, loss of Clns, or the presence of a cdc28 mutation increased cell growth specifically in smaller cells and accelerated meiosis in these cells. Finally, overexpression of CLNs repressed meiosis in smaller cells, but not in large cells. Taken together, these results demonstrate that Cln-Cdc28 represses entry into meiosis in part by inhibiting cell growth.


Asunto(s)
Proteína Quinasa CDC28 de Saccharomyces cerevisiae/metabolismo , Aumento de la Célula , Ciclinas/metabolismo , Meiosis , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/enzimología , Proteína Quinasa CDC28 de Saccharomyces cerevisiae/genética , Proliferación Celular , Ciclinas/genética , Silenciador del Gen , Mutación , Saccharomyces cerevisiae/crecimiento & desarrollo , Proteínas de Saccharomyces cerevisiae/genética , Factores de Tiempo , Transfección
12.
Biochem Biophys Res Commun ; 320(3): 893-9, 2004 Jul 30.
Artículo en Inglés | MEDLINE | ID: mdl-15240132

RESUMEN

Uracil-DNA glycosylase (Ung), a DNA repair enzyme, pioneers uracil excision repair pathway. Structural determinations and mutational analyses of the Ung class of proteins have greatly facilitated our understanding of the mechanism of uracil excision from DNA. More recently, a hybrid quantum-mechanical/molecular mechanical analysis revealed that while the histidine (H67 in EcoUng) of the GQDPYH motif (omega loop) in the active site pocket is important in positioning the reactants, it makes an unfavorable energetic contribution (penalty) in achieving the transition state intermediate. Mutational analysis of this histidine is unavailable from any of the Ung class of proteins. A complication in demonstrating negative role of a residue, especially when located within the active site pocket, is that the mutants with enhanced activity are rarely obtained. Interestingly, unlike the most Ung proteins, the H67 equivalent in the omega loop in mycobacterial Ung is represented by P67. Exploiting this natural diversity to maintain structural integrity of the active site, we transplanted an H67P mutation in EcoUng. Uracil inhibition assays and binding of a proteinaceous inhibitor, Ugi (a transition state substrate mimic), with the mutant (H67P) revealed that its active site pocket was not perturbed. The catalytic efficiency (Vmax/Km) of the mutant was similar to that of the wild type Ung. However, the mutant showed increased Km and Vmax. Together with the data from a double mutation H67P/G68T, these observations provide the first biochemical evidence for the proposed diverse roles of H67 in catalysis by Ung.


Asunto(s)
ADN Glicosilasas/química , Escherichia coli/enzimología , Histidina/química , Agua/química , Secuencia de Aminoácidos , Sustitución de Aminoácidos , Sitios de Unión , Catálisis , ADN Glicosilasas/genética , Activación Enzimática , Estabilidad de Enzimas , Escherichia coli/genética , Cinética , Datos de Secuencia Molecular , Mutagénesis Sitio-Dirigida , Unión Proteica , Estructura Secundaria de Proteína , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/química , Homología de Secuencia de Aminoácido , Relación Estructura-Actividad , Uracil-ADN Glicosidasa
13.
J Cell Sci ; 116(Pt 11): 2137-47, 2003 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-12730290

RESUMEN

Diploid yeast, like most eukaryotes, can undergo meiotic differentiation to form haploid gametes. Meiotic differentiation and cell growth (proliferation) are mutually exclusive programs, and in yeast the switch between growth and meiosis is controlled by nutritional signals. The signaling pathways that mediate nutritional controls on meiotic initiation fall into three broad classes: those that respond to nutrient starvation, those that respond to non-fermentable carbon sources, and those that respond to glucose. At the onset of meiosis, nutritional signaling pathways converge on transcriptional regulation of two genes: IME1, which encodes a transcription factor; and IME2, which encodes a protein kinase. Transcription of IME1 and IME2 trigger initiation of meiosis, and the expression of these two genes is linked with one other, with expression of later meiotic genes and with early meiotic events such as DNA replication. In addition, the signaling pathways that control IME1 and IME2 expression are themselves integrated through a variety of mechanisms. Thus the signal network that controls the switch from growth to meiotic differentiation provides a signaling code that translates different combinations of extracellular signals into appropriate cellular responses.


Asunto(s)
Meiosis/fisiología , Mitosis/fisiología , Transducción de Señal/fisiología , Levaduras/fisiología , Levaduras/crecimiento & desarrollo
14.
Curr Genet ; 42(1): 1-8, 2002 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-12420140

RESUMEN

As yeast colonies ceased growth, cells at the edge of these colonies transited from the cell division cycle into meiosis at high efficiency. This transition occurred remarkably synchronously and only at late stages of colony maturation. The transition occurred on medium containing acetate or low concentrations of glucose, but not on medium containing high glucose. The repression by high glucose was overcome when IME1 was overexpressed from a plasmid. Experiments with different growth media imply that meiosis in colonies is triggered by changes in the nutrient environment as colonies mature. HAP2 is required to sporulate in any carbon source, whereas GRR1 is required for glucose repression of sporulation. CLN3 is required to repress meiosis in colonies but not in liquid cultures, indicating that the regulators that mediate the transition to meiosis in colonies are not identical to the regulators that mediate this transition in liquid cultures.


Asunto(s)
Meiosis/fisiología , Saccharomyces cerevisiae/citología , Ubiquitina-Proteína Ligasas , Sulfato de Amonio/metabolismo , Factor de Unión a CCAAT/metabolismo , Proteínas Portadoras/metabolismo , Diferenciación Celular/fisiología , Ciclinas/metabolismo , Proteínas F-Box , Proteínas Fúngicas/metabolismo , Genes Reguladores , Glucosa/metabolismo , Haploidia , Mutación , Proteínas Serina-Treonina Quinasas/metabolismo , Saccharomyces cerevisiae/crecimiento & desarrollo , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo
15.
Genes Cells ; 7(7): 675-91, 2002 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-12081645

RESUMEN

BACKGROUND: IME1, which is required for the initiation of meiosis, is regulated by Cln3:Cdc28 kinase, which activates the G1-to-S transition, and Snf1 kinase, which mediates glucose repression. Here we examine the pathway by which Cln3:Cdc28p represses IME1 and the relationship between Cln3:Cdc28p and Snf1p in this regulation. RESULTS: When wild-type yeast cease growth, they express IME1 to moderate levels, intermediate between the low levels expressed during growth and the high levels expressed during sporulation. Moderate IME1 expression occurred in cln3Delta, cln1Delta cln2Delta, cdc28-4 and swi6Delta mutants, even during growth. These mutants also induced IME1 expression more rapidly than the wild-type. CLN3 required SWI6 and CLN2 to repress IME1 and IME2, but CLN1 was much less active than CLN2 in this repression. The phenotype of the cln3Delta snf1Delta double mutant indicated that Cln3:Cdc28p regulates IME1 independently of SNF1. CONCLUSION: Entry into meiosis involves two independent but sequential controls, which regulate IME1 via a three position switch: (i) during growth IME1 is repressed by the CLN3/SWI6/CLN2 pathway, (ii) once growth ceases, this repression is released and IME1 is expressed at moderate levels, and (iii) subsequently, nutritional conditions that activate Snf1p allow high IME1 expression.


Asunto(s)
Ciclinas/fisiología , Proteínas Fúngicas/fisiología , Meiosis/fisiología , Proteínas Nucleares/fisiología , Proteínas Serina-Treonina Quinasas/fisiología , Proteínas de Saccharomyces cerevisiae/fisiología , Saccharomyces cerevisiae/fisiología , Factores de Transcripción/fisiología , Proteína Quinasa CDC28 de Saccharomyces cerevisiae/metabolismo , Proteínas Fúngicas/biosíntesis , Proteínas Fúngicas/genética , Proteínas Nucleares/biosíntesis , Proteínas Nucleares/genética , Saccharomyces cerevisiae/citología , Transducción de Señal , Esporas Fúngicas
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