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Eusebio Chiefari,
Sinan Tanyolaç,
Stefania Iiritano,
Angela Sciacqua,
Carmelo Capula,
Biagio Arcidiacono,
Aurora Nocera,
Katiuscia Possidente,
Francesco Baudi,
Valeria Ventura, [......],
Raffaele Maio,
Manfredi Greco,
Maria Pavia,
Ugur Hodoglugil,
Vincent Durlach,
Clive R Pullinger,
Ira D Goldfine,
Francesco Perticone,
Daniela Foti,
Antonio Brunetti
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ABSTRACT: The metabolic syndrome (MetS) is a common disorder, where systemic insulin-resistance is associated with increased risk for type 2 diabetes (T2D) and cardiovascular disease. Identifying genetic traits influencing risk and progression of MetS is important. We and others previously reported a functional HMGA1 gene variant, rs146052672, predisposing to T2D. Here we investigated the association of rs146052672 variant with MetS and related components. In a case-control study from Italy and Turkey, increased risk of MetS was seen among carriers of the HMGA1 variant. In the larger Italian cohort, this variant positively correlated with BMI, hyperglycemia and insulin-resistance, and negatively correlated with serum HDL-cholesterol. Association between rs146052672 variant and MetS occurred independently of T2D, indicating that HMGA1 gene defects play a pathogenetic role in MetS and other insulin-resistance-related conditions. Overall, our results indicate that the rs146052672 variant represents an early predictive marker of MetS, as well as a predictive tool for therapy.
Scientific Reports 03/2013; 3:1491.
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Stefania Iiritano,
Eusebio Chiefari,
Valeria Ventura,
Biagio Arcidiacono,
Katiuscia Possidente,
Aurora Nocera,
Maria T Nevolo,
Monica Fedele,
Adelaide Greco,
Manfredi Greco, Giuseppe Brunetti,
Alfredo Fusco,
Daniela Foti,
Antonio Brunetti
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ABSTRACT: We previously showed that loss of the high mobility group A1 (HMGA1) protein expression, induced in mice by disrupting the Hmga1 gene, considerably decreased insulin receptor expression in the major target tissues of insulin action, causing a type 2-like diabetic phenotype, in which, however, glucose intolerance was paradoxically associated with increased peripheral insulin sensitivity. Insulin hypersensitivity despite impairment of insulin action supports the existence of molecular adaptation mechanisms promoting glucose disposal via insulin-independent processes. Herein, we provide support for these compensatory pathways/circuits of glucose uptake in vivo, the activation of which under certain adverse metabolic conditions may protect against hyperglycemia. Using chromatin immunoprecipitation combined with protein-protein interaction studies of nuclear proteins in vivo, and transient transcription assays in living cells, we show that HMGA1 is required for gene activation of the IGF-binding proteins 1 (IGFBP1) and 3 (IGFBP3), two major members of the IGF-binding protein superfamily. Furthermore, by using positron emission tomography with (18)F-labeled 2-fluoro-2-deoxy-d-glucose, in combination with the euglycemic clamp with IGF-I, we demonstrated that IGF-I's bioactivity was increased in Hmga1-knockout mice, in which both skeletal muscle Glut4 protein expression and glucose uptake were enhanced compared with wild-type littermates. We propose that, by affecting the expression of both IGFBP protein species, HMGA1 can serve as a modulator of IGF-I activity, thus representing an important novel mediator of glucose disposal.
Molecular Endocrinology 06/2012; 26(9):1578-89. · 4.54 Impact Factor
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Eusebio Chiefari,
Maria T Nevolo,
Biagio Arcidiacono,
Elisa Maurizio,
Aurora Nocera,
Stefania Iiritano,
Riccardo Sgarra,
Katiuscia Possidente,
Camillo Palmieri,
Francesco Paonessa, Giuseppe Brunetti,
Guidalberto Manfioletti,
Daniela Foti,
Antonio Brunetti
[show abstract]
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ABSTRACT: High-mobility group AT-hook 1 (HMGA1) protein is an important nuclear factor that activates gene transcription by binding to AT-rich sequences in the promoter region of DNA. We previously demonstrated that HMGA1 is a key regulator of the insulin receptor (INSR) gene and individuals with defects in HMGA1 have decreased INSR expression and increased susceptibility to type 2 diabetes mellitus. In addition, there is evidence that intracellular regulatory molecules that are employed by the INSR signaling system are involved in post-translational modifications of HMGA1, including protein phosphorylation. It is known that phosphorylation of HMGA1 reduces DNA-binding affinity and transcriptional activation. In the present study, we investigated whether activation of the INSR by insulin affected HMGA1 protein phosphorylation and its regulation of gene transcription. Collectively, our findings indicate that HMGA1 is a novel downstream target of the INSR signaling pathway, thus representing a new critical nuclear mediator of insulin action and function.
Scientific Reports 01/2012; 2:251.
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Eusebio Chiefari,
Francesco Paonessa,
Stefania Iiritano,
Le Pera Ilaria,
Dario Palmieri, Giuseppe Brunetti,
Angelo Lupo,
Vittorio Colantuoni,
Daniela Foti,
Elio Gulletta,
De Sarro Giovambattista,
Alfredo Fusco,
Antonio Brunetti
[show abstract]
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ABSTRACT: Abstract
Background
We previously showed that mice lacking the high mobility group A1 gene ( Hmga1 -knockout mice) developed a type 2-like diabetic phenotype, in which cell-surface insulin receptors were dramatically reduced (below 10% of those in the controls) in the major targets of insulin action, and glucose intolerance was associated with increased peripheral insulin sensitivity. This particular phenotype supports the existence of compensatory mechanisms of insulin resistance that promote glucose uptake and disposal in peripheral tissues by either insulin-dependent or insulin-independent mechanisms. We explored the role of these mechanisms in the regulation of glucose homeostasis by studying the Hmga1 -knockout mouse model. Also, the hypothesis that increased insulin sensitivity in Hmga1 -deficient mice could be related to the deficit of an insulin resistance factor is discussed.
Results
We first show that HMGA1 is needed for basal and cAMP-induced retinol-binding protein 4 ( RBP4 ) gene and protein expression in living cells of both human and mouse origin. Then, by employing the Hmga1 -knockout mouse model, we provide evidence for the identification of a novel biochemical pathway involving HMGA1 and the RBP4, whose activation by the cAMP-signaling pathway may play an essential role for maintaining glucose metabolism homeostasis in vivo , in certain adverse metabolic conditions in which insulin action is precluded. In comparative studies of normal and mutant mice, glucagon administration caused a considerable upregulation of HMGA1 and RBP4 expression both at the mRNA and protein level in wild-type animals. Conversely, in Hmga1 -knockout mice, basal and glucagon-mediated expression of RBP4 was severely attenuated and correlated inversely with increased Glut4 mRNA and protein abundance in skeletal muscle and fat, in which the activation state of the protein kinase Akt, an important downstream mediator of the metabolic effects of insulin on Glut4 translocation and carbohydrate metabolism, was simultaneously increased.
Conclusion
These results indicate that HMGA1 is an important modulator of RBP4 gene expression in vivo . Further, they provide evidence for the identification of a novel biochemical pathway involving the cAMP-HMGA1-RBP4 system, whose activation may play a role in glucose homeostasis in both rodents and humans. Elucidating these mechanisms has importance for both fundamental biology and therapeutic implications.
BMC Biology 01/2009; · 5.75 Impact Factor
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Francesco Paonessa,
Daniela Foti,
Vanessa Costa,
Eusebio Chiefari, Giuseppe Brunetti,
Francesco Leone,
Francesco Luciano,
Frank Wu,
Amy S Lee,
Elio Gulletta,
Alfredo Fusco,
Antonio Brunetti
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ABSTRACT: Various studies have shown that the insulin receptor (IR) is increased in most human breast cancers, and both ligand-dependent malignant transformation and increased cell growth occur in cultured breast cells overexpressing the IR. However, although numerous in vivo and in vitro observations have indicated an important contributory role for the IR in breast cancer cell biology, the molecular mechanisms accounting for increased IR expression in breast tumors have not previously been elucidated. Herein, we did immunoblot analyses of nuclear protein from cultured breast cancer cells and normal and tumoral tissues from breast cancer patients combined with promoter studies by using a series of human wild-type and mutant IR promoter constructs. We provide evidence that IR overexpression in breast cancer is dependent on the assembly of a transcriptionally active multiprotein-DNA complex, which includes the high-mobility group A1 (HMGA1) protein, the developmentally regulated activator protein-2 (AP-2) transcription factor and the ubiquitously expressed transcription factor Sp1. In cultured breast cancer cells and human breast cancer specimens, the expression of AP-2 was significantly higher than that observed in cells and tissues derived from normal breast, and this overexpression paralleled the increase in IR expression. However, AP-2 DNA-binding activity was undetectable with the IR gene promoter, suggesting that transactivation of this gene by AP-2 might occur indirectly through physical and functional cooperation with HMGA1 and Sp1. Our findings support this hypothesis and suggest that in affected individuals, hyperactivation of the AP-2 gene through the overexpression of IR may play a key role in breast carcinogenesis.
Cancer Research 06/2006; 66(10):5085-93. · 7.86 Impact Factor
