Assuntos
Diabetes Mellitus Tipo 2/prevenção & controle , Hipoglicemiantes/uso terapêutico , Estilo de Vida , Metformina/uso terapêutico , Obesidade/terapia , Aprovação de Drogas , Intolerância à Glucose/complicações , Intolerância à Glucose/terapia , Humanos , Cobertura do Seguro , Pessoa de Meia-Idade , Obesidade/complicações , Uso Off-Label , Sobrepeso/complicações , Sobrepeso/terapia , Estados UnidosAssuntos
Disparidades em Assistência à Saúde , National Institute of Diabetes and Digestive and Kidney Diseases (U.S.) , Pesquisa Biomédica , Doença Crônica , Protocolos Clínicos , Estudos de Coortes , Feminino , Mão de Obra em Saúde , Humanos , Masculino , Grupos Minoritários , Saúde das Minorias , Estados Unidos , Recursos HumanosRESUMO
A cytoplasmic activity in mature oocytes responsible for second meiotic metaphase arrest was identified over 30 years ago in amphibian oocytes. In Xenopus oocytes cytostatic factor (CSF) activity is initiated by the progesterone-dependent synthesis of Mos, a MAPK kinase kinase that activates the MAPK pathway. CSF arrest is mediated by a sole MAPK target, the protein kinase p90(Rsk). Rsk phosphorylates and activates the Bub1 protein kinase, which may cause metaphase arrest due to inhibition of the anaphase-promoting complex (APC) by a conserved mechanism defined genetically in yeast and mammalian cells. CSF arrest in vertebrate oocytes by p90(Rsk) provides a link between the MAPK pathway and the spindle assembly checkpoint in the cell cycle.
Assuntos
Meiose , Oócitos/citologia , Proteínas Proto-Oncogênicas c-mos/fisiologia , Vertebrados/fisiologia , Animais , Ciclo Celular/fisiologia , Feminino , Humanos , Sistema de Sinalização das MAP Quinases/fisiologia , Oócitos/metabolismoAssuntos
Diabetes Mellitus Tipo 1 , Angiopatias Diabéticas/patologia , Angiopatias Diabéticas/terapia , Biomarcadores , Ensaios Clínicos como Assunto/métodos , Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 1/terapia , Endotélio Vascular/fisiopatologia , Guias como Assunto , Humanos , Resistência à Insulina , National Institutes of Health (U.S.) , Estados UnidosRESUMO
Known prions (infectious proteins) are self-propagating amyloids or conformationally altered proteins, but in theory an enzyme necessary for its own activation could also be a prion (or a gene composed of protein). We show that yeast protease B is such a prion, called [beta].[beta] is infectious, reversibly curable, and its de novo generation is induced by overexpression of the pro-protease. Present in normal cells but masked by the functionally redundant protease A, [beta] is advantageous during starvation and necessary for sporulation. We propose that other enzymes whose active, modified, form is necessary for their maturation might also be prions.
Assuntos
Endopeptidases/metabolismo , Príons/metabolismo , Leveduras/metabolismo , Fenótipo , Príons/biossínteseRESUMO
[URE3] and [PSI(+)] are infectious protein forms of the Saccharomyces cerevisiae Ure2p and Sup35p, respectively. We isolated an allele of SSA2, the primary cytosolic Hsp70, in a screen for mutants unable to maintain [URE3]. Designated ssa2-10, the mutation results in a leucine substitution for proline 395, a conserved residue of the peptide-binding domain. This allele also unexpectedly destabilizes [URE3] in newly formed heterozygotes: [URE3] is either absent in heterozygotes formed by crossing wild-type [URE3] cells with ssa2-10 mutants, or present and fully stable. SSA2 deletion mutants are weakly capable of maintaining [URE3]. The ssa2-10 allele is compatible with propagation of [PSI(+)]. However, in combination with a deletion of SSA1, ssa2-10 eliminates the nonsense-suppression phenotype of [PSI(+)] cells.
Assuntos
Proteínas Fúngicas/genética , Regulação Fúngica da Expressão Gênica/fisiologia , Proteínas de Choque Térmico HSP70/genética , Príons/genética , Saccharomyces cerevisiae/genética , Clonagem Molecular , DNA Fúngico/química , DNA Fúngico/genética , Proteínas Fúngicas/química , Proteínas Fúngicas/metabolismo , Proteínas de Choque Térmico HSP70/química , Mutação Puntual , Reação em Cadeia da Polimerase , Príons/metabolismo , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae , Supressão GenéticaRESUMO
Yeast infectious protein (prion) forms of the Ure2 and Sup35 proteins determine the nonchromosomal genes [URE3] and [PSI], and these are, therefore, the basis for a kind of epigenetic phenomena. In many systems, introduction of multiple copies of a DNA gene, or dsRNA copies of its sequence, results in the epigenetic silencing of that gene. In parallel with these homology effects, which act at the level of DNA or RNA, elevated copy number of the Ure2 and Sup35 proteins increases the frequency of their own "silencing" by prion formation. Both [URE3] and [PSI] appear to be due to self-propagating-amyloid formation of Ure2p and Sup35p, respectively. Another prion, [Het-s] of the filamentous fungus, Podospora anserina, is necessary for a normal cellular function, heterokaryon incompatibility. Since these prions are nonchromosomal genes, they are proteins acting as genes, a parallel to the fact that nucleic acids can catalyze enzymatic reactions.