PKA-dependent and independent cAMP signaling in 3T3-L1 fibroblasts differentiation

Martini, Claudia; Plaza, Maria V.; Vila, María del Carmen

doi:10.1016/j.mce.2008.10.023

Cited by 51 publications

(42 citation statements)

References 21 publications

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“…Epac1 Ϫ/Ϫ deficiency also results in smaller epididymal adipocyte size in vivo. Previous studies using 3T3-L1 preadipocytes in vitro suggested that Epac1 is important in regulating adipocyte differentiation (46)(47)(48). However, our results using isolated MEF cells ex vivo demonstrate that Epac1 does not play a critical role in adipocyte differentiation.…”

Section: Fig 8 Epac1contrasting

confidence: 89%

Enhanced Leptin Sensitivity, Reduced Adiposity, and Improved Glucose Homeostasis in Mice Lacking Exchange Protein Directly Activated by Cyclic AMP Isoform 1

Yan

Mei

Cheng

et al. 2013

Molecular and Cellular Biology

106

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The prototypic second messenger cyclic AMP (cAMP) is essential for controlling cellular metabolism, including glucose and lipid homeostasis. In mammals, the majority of cAMP functions are mediated by cAMP-dependent protein kinase (PKA) and exchange proteins directly activated by cAMP (Epacs). To explore the physiological functions of Epac1, we generated Epac1 knockout mice. Here we report that Epac1 null mutants have reduced white adipose tissue and reduced plasma leptin levels but display heightened leptin sensitivity. Epac1-deficient mice are more resistant to high-fat diet-induced obesity, hyperleptinemia, and glucose intolerance. Furthermore, pharmacological inhibition of Epac by use of an Epac-specific inhibitor reduces plasma leptin levels in vivo and enhances leptin signaling in organotypic hypothalamic slices. Taken together, our results demonstrate that Epac1 plays an important role in regulating adiposity and energy balance. Obesity is a grave health problem, as it is closely related to the leading causes of morbidity and mortality, such as cardiovascular diseases, type 2 diabetes, hypertension, depression, and cancer (1). Over the last 2 decades, obesity has reached epidemic proportions in the United States: more than 35% of adults in the United States are obese, and more than two-thirds are overweight (2). Furthermore, 500 million people worldwide are obese, representing approximately 12% of the adult population on earth (3). Chronic excessive food/energy intake, mediated by leptin resistance, is a major factor contributing to obesity. To date, few effective treatment options are available for obesity (4). Therefore, a better understanding of the underlying molecular mechanisms of obesity development and effective, safe therapeutic interventions are urgently needed. Cyclic AMP (cAMP)-mediated signaling pathways are important for maintaining metabolic homeostasis and have been implicated in regulating leptin production and secretion (5-7). In mammals, the majority of cAMP functions are mediated by cAMP-dependent protein kinase (PKA) and exchange proteins directly activated by cAMP (Epacs) (8-10). A recent study revealed that activation of Epacs by an Epac-selective cAMP analog, 8-CPT-2=-O-Me-cAMP (11), interferes with leptin signaling in the hypothalamus, suggesting that Epacs may contribute to the pathophysiology of leptin resistance and represent a novel pharmacological target for treatment of obesity (12). To investigate the functional significance of Epac1 in leptin-mediated energy balance in vivo, we generated global loss-of-function mutants for Epac1. Analysis of these animals indicated resistance to high-fat diet (HFD)-induced obesity, heightened leptin signaling in the arcuate nucleus (AN), and improved glucose tolerance. These findings reveal an important role of Epac1 in metabolism and suggest that Epac1 may represent a novel therapeutic target for obesity. MATERIALS AND METHODS Mice.To construct an Epac1 targeting vector, two loxP sites were inserted into introns 2 and 5. A 3.8-kb upstream ...

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Section: Fig 8 Epac1contrasting

confidence: 89%

Enhanced Leptin Sensitivity, Reduced Adiposity, and Improved Glucose Homeostasis in Mice Lacking Exchange Protein Directly Activated by Cyclic AMP Isoform 1

Yan

Mei

Cheng

et al. 2013

Molecular and Cellular Biology

106

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“…This suggests that Mfn2 is an important protein in the Ras-signaling pathway. Furthermore, it is known that Mfn2 contains a PKA phosphorylation site at Ser442 (33)(34)(35)(36) and the cAMP-PKA signaling pathway is a versatile signal pathway involved in regulation of cellular functions through phosphorylation (44)(45)(46)(47)(48). The present study demonstrated that the PKA phosphorylation site at Ser442 of Mfn2 was essential for Mfn2-mediated inhibition of ERK1/2 signaling and reduced proliferation of breast cancer cells.…”

Section: Discussionsupporting

confidence: 50%

The anti-tumor effects of Mfn2 in breast cancer are dependent on promoter DNA methylation, the P21Ras motif and PKA phosphorylation site

Dong

Shan

et al. 2018

Oncol Lett

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Abstract. Mitofusin 2 (Mfn2) is expressed in numerous human tissues and serves a pivotal role in cell proliferation. However, Mfn2 is considered as an anti-tumor gene, and is silenced in human malignant tumors, including those of breast cancer. However, the mechanisms contributing to Mfn2 silencing and the mechanism of its anti-tumor function in breast cancer remain unclear. In the present study, hypoexpression of Mfn2, and hypermethylation of its promoter, was confirmed in human breast cancer cells and in breast cancer tissues by reverse transcription-quantitative polymerase chain reaction (PCR) and methylation specific PCR, respectively. Chemical demethylation treatment with 5-aza-2'-deoxycytidine upregulated the mRNA expression level of Mfn2 in MCF-7 cells in a dose-dependent manner. In addition, overexpression of Mfn2 repressed the proliferation, migration and invasion of MCF-7 cells, mediated by inhibition of the Ras-extracellular signal-regulated kinase (ERK)1/2 signaling pathway. However, overexpression of Mfn2 with deletion of the p21Ras motif (Mfn2 ΔRas ) and protein kinase A (PKA) phosphorylation site (Mfn2 ΔPKA ) partially reduced the anti-tumor function of Mfn2, and inhibited the Ras-ERK1/2 signaling pathway. Taken together, the present study confirmed the anti-tumor effects of Mfn2 in human breast cancer and clarified that the mechanism of its anti-tumor functions includes promoter DNA methylation, the P21 Ras binding site and PKA phosphorylation.

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“…UVA Irradiation Up-regulates MIF Expression during Adipocyte Differentiation-Several molecular targets for anti-adipogenesis have been reported, namely TNF-␣, IL-1␤, VEGF, TGF-␤1, and MIF (5,20,21). Therefore, we evaluated UVA irradiation to determine whether it exerted a stimulatory effect on production of the aforementioned cytokines.…”

Section: Effects Of Uva Irradiation On the Expression Of The Adipogenmentioning

confidence: 99%

Ultraviolet A Regulates Adipogenic Differentiation of Human Adipose Tissue-derived Mesenchymal Stem Cells via Up-regulation of Kruppel-like Factor 2

Lee

Jung

et al. 2010

Journal of Biological Chemistry

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Adipocyte dysfunction is strongly associated with the development of obesity, which is a major risk factor for many disorders, including diabetes, hypertension, and heart disease. This study shows that ultraviolet A (UVA) inhibits adipogenic differentiation of human adipose tissue-derived mesenchymal stem cells and its action mechanisms. The mRNA levels of peroxidase proliferator-activated receptor (PPAR) ␥ and CCAAT/enhancer -binding protein ␣ (C/EBP␣), but not CCAAT/enhancer-binding protein ((C/EBP) ␤ and ␦, were reduced by UVA. Moreover, the mRNA levels of PPAR ␥ target genes (lipoprotein lipase (LPL), CD36, adipocyte protein (aP2), and liver X receptor ␣ (LXR)) were down-regulated by UVA. Additionally, attempts to elucidate a possible mechanism underlying the UVA-mediated effects revealed that UVA induced migration inhibitory factor (MIF) gene expression, and this was mediated through activation of AP-1 (especially JNK and p42/44 MAPK) and nuclear factor-B. In addition, reduced adipogenesis by UVA was recovered upon the treatment with anti-MIF antibodies. AMP-activated protein kinase phosphorylation and up-regulation of Kruppel-like factor 2 (KLF2) were induced by UVA. Taken together, these findings suggest that the inhibition of adipogenic differentiation of human adipose tissue-derived mesenchymal stem cells by UVA occurs primarily through the reduced expression of PPAR ␥, which is mediated by up-regulation of KLF2 via the activation of MIF-AMP-activated protein kinase signaling.

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PKA-dependent and independent cAMP signaling in 3T3-L1 fibroblasts differentiation

Cited by 51 publications

References 21 publications

Enhanced Leptin Sensitivity, Reduced Adiposity, and Improved Glucose Homeostasis in Mice Lacking Exchange Protein Directly Activated by Cyclic AMP Isoform 1

Enhanced Leptin Sensitivity, Reduced Adiposity, and Improved Glucose Homeostasis in Mice Lacking Exchange Protein Directly Activated by Cyclic AMP Isoform 1

The anti-tumor effects of Mfn2 in breast cancer are dependent on promoter DNA methylation, the P21Ras motif and PKA phosphorylation site

Ultraviolet A Regulates Adipogenic Differentiation of Human Adipose Tissue-derived Mesenchymal Stem Cells via Up-regulation of Kruppel-like Factor 2

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