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1.
Diabetes ; 53(1): 245-9, 2004 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-14693723

RESUMO

The adipocyte hormone leptin constitutes an important component of the regulation of energy homeostasis; leptin-deficient animals, such as obese mice, are strikingly overweight. The seemingly uninhibited weight gain in obese mice belies the fact that control of energy homeostasis remains under precise, heritably modifiable control. Herein, we report large, heritable differences in body weight and food intake between BTBR-ob/ob and B6-ob/ob mice. We have identified two loci, called modifier of obese (Moo1 and Moo2), that explain the majority of the heritable variance in (BTBR x B6) F(2)-ob/ob mice. Using interval-specific congenic mouse lines, we mapped Moo1 to an 8-Mb segment of chromosome 2 and demonstrated that Moo1 exerts its effects primarily by regulating total fat mass. Although null alleles of leptin are rare, the majority of overweight adults are leptin resistant, suggesting that leptin-independent pathways, such as those studied here, are important regulators of energy homeostasis. Thus, the identification of these loci may provide important new insights into the pathogenesis of human obesity.


Assuntos
Peso Corporal/genética , Camundongos Obesos/genética , Locos de Características Quantitativas/genética , Envelhecimento , Animais , Ingestão de Energia , Feminino , Variação Genética/genética , Crescimento/genética , Masculino , Camundongos , Caracteres Sexuais
2.
J Biol Chem ; 283(13): 8678-86, 2008 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-18218622

RESUMO

Phosphoinositide signaling pathways regulate numerous processes in eukaryotic cells, including migration, proliferation, and survival. The regulatory lipid phosphatidylinositol 4,5-bisphosphate is synthesized by two distinct classes of phosphatidylinositol phosphate kinases (PIPKs), the type I and II PIPKs. Although numerous physiological functions have been identified for type I PIPKs, little is known about the functions and regulation of type II PIPK. Using a yeast two-hybrid screen, we identified an interaction between the type IIbeta PIPK isoform (PIPKIIbeta) and SPOP (speckle-type POZ domain protein), a nuclear speckle-associated protein that recruits substrates to Cul3-based ubiquitin ligases. PIPKIIbeta and SPOP interact and co-localize at nuclear speckles in mammalian cells, and SPOP mediates the ubiquitylation of PIPKIIbeta by Cul3-based ubiquitin ligases. Additionally, stimulation of the p38 MAPK pathway enhances the ubiquitin ligase activity of Cul3-SPOP toward multiple substrate proteins. Finally, a kinase-dead PIPKIIbeta mutant enhanced ubiquitylation of Cul3-SPOP substrates. The kinase-dead PIPKIIbeta mutant increases the cellular content of its substrate lipid phosphatidylinositol 5-phosphate (PI5P), suggesting that PI5P may stimulate Cul3-SPOP activity through a p38-dependent signaling pathway. Expression of phosphatidylinositol-4,5-bisphosphate 4-phosphatases that generate PI5P dramatically stimulated Cul3-SPOP activity and was blocked by the p38 inhibitor SB203580. Taken together, these data define a novel mechanism whereby the phosphoinositide PI5P leads to stimulation of Cul3-SPOP ubiquitin ligase activity and also implicate PIPKIIbeta as a key regulator of this signaling pathway through its association with the Cul3-SPOP complex.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Proteínas Culina/metabolismo , Proteínas Nucleares/metabolismo , Fosfatos de Fosfatidilinositol/metabolismo , Proteínas Repressoras/metabolismo , Transporte Ativo do Núcleo Celular , Proteínas de Ciclo Celular/genética , Linhagem Celular , Proteínas Culina/genética , Ativação Enzimática , Humanos , Imidazóis/farmacologia , MAP Quinase Quinase 6/metabolismo , Proteínas Nucleares/genética , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Ligação Proteica , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Proteínas Repressoras/genética , Sensibilidade e Especificidade , Transdução de Sinais/efeitos dos fármacos , Especificidade por Substrato , Ubiquitinação , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
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