Publications (21) View all
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Article: DARPP-32 is required for MAPK/ERK signaling in thyroid cells.
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ABSTRACT: Modulation of MAPK signaling duration by cAMP defines its physiological output by driving cells toward proliferation or differentiation. Understanding how the kinetics of MAPK signaling are integrated with other cellular signals is a key issue in development and cancer. Here we show that dopamine and cAMP-regulated neuronal phosphoprotein, 32 kDa (DARPP-32), a protein required for thyroid cell differentiation, determines whether MAPK/ERK activation is sustained or transient. Serum, a stimulus that activates MAPK signaling and does not independently increase DARPP-32 levels results in transient activation of the MAPK pathway. By contrast, TSH + (IGF-I) activate MAPK signaling but also independently increase DARPP-32 levels. Our results are consistent with a model in which maintenance of DARPP-32 expression by TSH + IGF-I leads to sustained MAPK signaling. Moreover, the sensitivity of MAPK/ERK signaling in thyroid cells is lost when de novo DARPP-32 expression is blocked by small interfering RNA. Because both DARPP-32 levels and function as inhibitor of protein phosphatase 1, a key inhibitor of MAPK kinase activity, are governed by cAMP/protein kinase A, the results may explain why in thyroid cells cAMP signaling downstream from TSH controls the duration of MAPK pathway activity. Thus, fine-tuning of DARPP-32 levels leads to changes in the kinetics or sensitivity of MAPK/ERK signaling. Given the implications of MAPK signaling in thyroid cancer and the loss of DARPP-32 in tumor and transformed thyroid cells, DARPP-32 may represent a key therapeutic target.Molecular Endocrinology 03/2012; 26(3):471-80. · 4.54 Impact Factor -
Article: Wnt and incretin connections.
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ABSTRACT: WNT signaling is emerging as a global regulator of metabolism, targeting multiple tissues. This is achieved either directly through Wnt receptors, or indirectly through the action of incretins, hormones that enhance glucose-stimulated insulin secretion and target extrapancreatic organs that cooperatively control whole body energy balance. WNT increases expression of incretins through evolutionarily conserved elements located within their proximal promoters. Wnt-responsive elements at the Incretin promoters may exhibit a high degree of selectivity for specific WNT effectors. Additionally, Incretins may modulate Wnt signaling and vice versa. Wnt-dependent modulation of incretin action in β-pancreatic cells is suspected because the expression levels of Incretin receptors correlate with those of the Wnt effector TCF7L2. Conversely, Wnt signaling is enhanced by Incretin binding to their receptors which induces cAMP accumulation followed by stabilization of the Wnt effector: β-catenin. High glucose and/or lipids control the number of Incretin receptors exhibited by β cells. Whether these nutrients and/or the Incretins control Wnt receptors (either their expression or signaling) remains to be further elucidated. Thus, Wnt controls the expression of incretins and modulate their signaling at pancreatic cells. Signaling by Wnt and incretins appears to be interconnected at multiple levels. The in vivo significance of incretin induction by Wnt is unknown as it is the nature and origin of Wnt signals in enteroendocrine cells but opens an intense research that promises many surprises; in vitro approaches may be used for mechanistic studies and animal models for physiological perspectives.Vitamins & Hormones 01/2010; 84:355-87. · 2.19 Impact Factor -
Article: WNT/beta-catenin increases the production of incretins by entero-endocrine cells.
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ABSTRACT: Glucose-dependent insulinotropic peptide (GIP) plays a pivotal role in the regulation of glucose homeostasis. Rates of diet-induced obesity, insulin resistance and type 2 diabetes are decreased when GIP signalling is disturbed in mice, suggesting that GIP plays a role in the onset of type 2 diabetes. WNT signalling is linked to type 2 diabetes and induces synthesis of the other incretin, glucagon-like peptide 1 (GLP-1). GLP-1 analogues improve treatment of type 2 diabetes patients in whom GLP-1 signalling is intact and have captured clinical attention. GIP levels are altered at the onset of type 2 diabetes and later on, while GIP signalling is impaired. Thus, GIP is not a candidate for treatment but might be an important target from a prevention perspective. Hypothesising that hypersecretion of GIP links altered WNT signalling to the onset of type 2 diabetes, we sought to determine whether WNT signalling induces GIP production by entero-endocrine cells. RT-PCR and chromatin immunoprecipitation (ChIP) were used to study Gip gene induction. Gip promoter elements mediating WNT/lithium induction were identified (electrophoretic mobility shift assay, co-transfection of deletion mutants, ChIP). Lithium or WNT/beta-catenin signalling enhanced GIP production by entero-endocrine cells through a conserved site in the proximal Gip promoter. Lithium favours lymphoid enhancer factor-1/beta-catenin binding to Gip promoter and diminishes ChIP through T cell factor-4 and histone deacetylase 1. Lithium and WNT are incretin inducers in general. This work provides a novel link between WNT signalling, obesity and diabetes.Diabetologia 08/2009; 52(9):1913-24. · 6.81 Impact Factor -
Article: Leukemia: the sophisticated subversion of hematopoiesis by nuclear receptor oncoproteins.
Biochimica et Biophysica Acta 02/1999; 1423(1):F15-33. · 4.66 Impact Factor -
Article: Regulation of malic-enzyme-gene expression by cAMP and retinoic acid in differentiating brown adipocytes.
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ABSTRACT: Brown adipose tissue (BAT) is composed of highly specialized cells, whose main function is to produce heat under adrenergic stimulation, uncoupling oxidative phosphorylation. For this function, lipogenesis must be accurately regulated. Malic enzyme has a central role in lipogenesis and is strongly expressed in brown adipocytes. In this work, we study the modulation by adrenergic stimuli, cAMP effectors and retinoic acid on the induction produced by insulin and 3,5,3'-triiodothyronine on malic-enzyme-gene expression. Primary cultures of differentiating brown adipocytes have been used. The results obtained demonstrate that physiological doses of norepinephrine do not modify malic-enzyme mRNA levels when acting alone, but considerably reduce the induction produced by insulin, 3,5,3'-triiodothyronine or both together. Other cAMP inducers such as glucagon, forskolin or 8-bromo-cAMP, greatly inhibit both, basal and 3,5,3'-triiodothyronine-induced malic-enzyme-gene gene expression. Retinoic acid abolishes basal and also inhibits 3,5,3'-triiodothyronine-induced malic-enzyme-gene expression.European Journal of Biochemistry 08/1993; 215(2):285-90. · 3.58 Impact Factor
