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1.
Growth Horm IGF Res ; 17(5): 399-407, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17560154

RESUMO

Rabson-Mendenhall syndrome is a rare genetic disorder characterized by severe insulin resistance and hyperinsulinemia due to defects in signaling through the insulin receptor. Herein, we describe a new case of Rabson-Mendenhall syndrome in which investigations of the growth hormone (GH) - insulin-like growth factor (IGF) axis - reveal severe deficiencies in total and free insulin-like growth factor-I (IGF-I), IGF-II, IGF-binding protein-3 (IGFBP-3), and the acid labile subunit (ALS). Based on these findings, we anticipated significant bone deficits, as have been described in other clinical scenarios in which the IGF axis is significantly perturbed. Long-bone studies revealed no gross malformations. Paradoxically, DXA scanning revealed a total body bone density Z-score of +2.0 (0.8 gm/cm(2)), suggesting an overall high-normal BMD for age and a high BMD corrected for bone or height age. The mechanisms by which BMD is protected from severe deficiencies in the IGF-axis are unknown, yet may involve enhanced IGF sensitivity, increased local production of IGFs, and/or supra-physiological concentrations of insulin substituting for the actions of IGFs in bone.


Assuntos
Densidade Óssea , Hiperinsulinismo/genética , Resistência à Insulina/genética , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/deficiência , Fator de Crescimento Insulin-Like II/deficiência , Fator de Crescimento Insulin-Like I/deficiência , Estatura , Tamanho Corporal , Peso Corporal , Criança , Pré-Escolar , DNA/genética , DNA/isolamento & purificação , Feminino , Humanos , Lactente , Resistência à Insulina/fisiologia , Masculino , Linhagem , Subunidades Proteicas , Síndrome
2.
Mol Cell Biol ; 21(5): 1682-7, 2001 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-11238905

RESUMO

The actinin-associated LIM protein, ALP, is the prototype of a large family of proteins containing an N-terminal PDZ domain and a C-terminal LIM domain. These PDZ-LIM proteins are components of the muscle cytoskeleton and occur along the Z lines owing to interaction of the PDZ domain with the spectrin-like repeats of alpha-actinin. Because PDZ and LIM domains are typically found in proteins that mediate cellular signaling, PDZ-LIM proteins are suspected to participate in muscle development. Interestingly the ALP gene occurs at 4q35 near the heterochromatic region mutated in facioscapulohumeral muscular dystrophy, indicating a possible role for ALP in this disease. Here, we describe the generation and analysis of mice lacking the ALP gene. Surprisingly, the ALP knockout mice show no gross histological abnormalities and maintain sarcolemmal integrity as determined by serum pyruvate kinase assays. The absence of a dystrophic phenotype in these mice suggests that down-regulation of ALP does not participate in facioscapulohumeral muscular dystrophy. These data suggest that ALP does not participate in muscle development or that an alternative PDZ-LIM protein can compensate for the lack of ALP.


Assuntos
Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Músculo Esquelético/metabolismo , Animais , Western Blotting , Mapeamento Cromossômico , Citoesqueleto/metabolismo , Regulação para Baixo , Vetores Genéticos , Genótipo , Humanos , Imuno-Histoquímica , Proteínas com Domínio LIM , Camundongos , Camundongos Knockout , Proteínas dos Microfilamentos/química , Microscopia de Fluorescência , Modelos Genéticos , Músculos/embriologia , Músculos/fisiologia , Distrofias Musculares/genética , Fenótipo , Estrutura Terciária de Proteína , Piruvato Quinase/sangue , Recombinação Genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa
3.
Mol Biol Cell ; 10(4): 819-32, 1999 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-10198040

RESUMO

Subcellular targeting and the activity of facilitative glucose transporters are likely to be regulated by interactions with cellular proteins. This report describes the identification and characterization of a protein, GLUT1 C-terminal binding protein (GLUT1CBP), that binds via a PDZ domain to the C terminus of GLUT1. The interaction requires the C-terminal four amino acids of GLUT1 and is isoform specific because GLUT1CBP does not interact with the C terminus of GLUT3 or GLUT4. Most rat tissues examined contain both GLUT1CBP and GLUT1 mRNA, whereas only small intestine lacked detectable GLUT1CBP protein. GLUT1CBP is also expressed in primary cultures of neurons and astrocytes, as well as in Chinese hamster ovary, 3T3-L1, Madin-Darby canine kidney, Caco-2, and pheochromocytoma-12 cell lines. GLUT1CBP is able to bind to native GLUT1 extracted from cell membranes, self-associate, or interact with the cytoskeletal proteins myosin VI, alpha-actinin-1, and the kinesin superfamily protein KIF-1B. The presence of a PDZ domain places GLUT1CBP among a growing family of structural and regulatory proteins, many of which are localized to areas of membrane specialization. This and its ability to interact with GLUT1 and cytoskeletal proteins implicate GLUT1CBP in cellular mechanisms for targeting GLUT1 to specific subcellular sites either by tethering the transporter to cytoskeletal motor proteins or by anchoring the transporter to the actin cytoskeleton.


Assuntos
Proteínas de Transporte/metabolismo , Citoesqueleto/metabolismo , Proteínas de Transporte de Monossacarídeos/metabolismo , Neuropeptídeos , Células 3T3 , Proteínas Adaptadoras de Transdução de Sinal , Sequência de Aminoácidos , Animais , Astrócitos/metabolismo , Sequência de Bases , Células CHO , Proteínas de Transporte/química , Proteínas de Transporte/genética , Linhagem Celular , Cricetinae , Cães , Transportador de Glucose Tipo 1 , Humanos , Masculino , Camundongos , Dados de Sequência Molecular , Proteínas de Transporte de Monossacarídeos/genética , Neurônios/metabolismo , Especificidade de Órgãos , Feocromocitoma , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/metabolismo , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Transfecção , Células Tumorais Cultivadas
5.
J Biol Chem ; 271(19): 11414-21, 1996 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-8626697

RESUMO

Turnover numbers for 3-O-methylglucose transport by the homologous glucose transporters GLUT1 and GLUT4 were compared to those for truncated and chimeric transporters expressed in Xenopus oocytes to assess potential regulatory properties of the C-terminal domain. The ability of high intracellular sugar concentrations to increase the turnover number for sugar entry ("accelerated exchange") by GLUT1 and not by GLUT4 was maintained in oocytes. Replacing the GLUT1 C terminus with that of GLUT4 stimulated turnover 1.6-fold, but abolished accelerated exchange. Thus, the GLUT1 C terminus permits accelerated exchange by GLUT1, but in doing so must interact with other GLUT1 specific sequences since the GLUT4ctrm1 chimera did not exhibit this kinetic property. Removal of 38 C-terminal amino acids from GLUT4 reduced its turnover number by 40%, whereas removing only 20 residues or replacing its C terminus with that of GLUT1 increased its turnover number 3.5-3.9 fold. Therefore, using mechanisms independent of those which alter transporter targeting to the plasma membrane, C-terminal mutations in either GLUT1 or GLUT4 can activate transport normally restricted by the native C-terminal domain. These results implicate the C termini as targets of physiological factors, which through covalent modification or direct binding might alter C-terminal interactions to regulate intrinsic GLUT1 and GLUT4 transporter activity.


Assuntos
Metilglucosídeos/metabolismo , Proteínas de Transporte de Monossacarídeos/metabolismo , Proteínas Musculares , Oócitos/metabolismo , 3-O-Metilglucose , Sequência de Aminoácidos , Animais , Anticorpos , Transporte Biológico , Membrana Celular/metabolismo , Sequência Conservada , Feminino , Transportador de Glucose Tipo 1 , Transportador de Glucose Tipo 4 , Cinética , Camundongos , Modelos Estruturais , Dados de Sequência Molecular , Proteínas de Transporte de Monossacarídeos/análise , Proteínas de Transporte de Monossacarídeos/química , Mutagênese , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/imunologia , Biossíntese de Proteínas , Estrutura Secundária de Proteína , Proteínas Recombinantes de Fusão/análise , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/metabolismo , Homologia de Sequência de Aminoácidos , Transcrição Gênica , Xenopus laevis
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