scholarly journals MKP-1 mediates glucocorticoid-induced ERK1/2 dephosphorylation and reduction in pancreatic β-cell proliferation in islets from early lactating mothers

2010 ◽  
Vol 299 (6) ◽  
pp. E1006-E1015 ◽  
Author(s):  
José E. Nicoletti-Carvalho ◽  
Camilo Lellis-Santos ◽  
Tatiana S. Yamanaka ◽  
Tatiane C. Nogueira ◽  
Luciana C. Caperuto ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Pancreatic Islets ◽  
Chromatin Immunoprecipitation ◽  
Protein Phosphatase ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Chromatin Immunoprecipitation Assay ◽  
Isolated Pancreatic Islets ◽  
Immunoprecipitation Assay ◽  
Lactating Mothers

Maternal pancreatic islets undergo a robust increase of mass and proliferation during pregnancy, which allows a compensation of gestational insulin resistance. Studies have described that this adaptation switches to a low proliferative status after the delivery. The mechanisms underlying this reversal are unknown, but the action of glucocorticoids (GCs) is believed to play an important role because GCs counteract the pregnancy-like effects of PRL on isolated pancreatic islets maintained in cell culture. Here, we demonstrate that ERK1/2 phosphorylation (phospho-ERK1/2) is increased in maternal rat islets isolated on the 19th day of pregnancy. Phospho-ERK1/2 status on the 3rd day after delivery (L3) rapidly turns to values lower than that found in virgin control rats (CTL). MKP-1, a protein phosphatase able to dephosphorylate ERK1/2, is increased in islets from L3 rats. Chromatin immunoprecipitation assay revealed that binding of glucocorticoid receptor (GR) to MKP-1 promoter is also increased in islets from L3 rats. In addition, dexamethasone (DEX) reduced phospho-ERK1/2 and increased MKP-1 expression in RINm5F and MIN-6 cells. Inhibition of transduction with cycloheximide and inhibition of phosphatases with orthovanadate efficiently blocked DEX-induced downregulation of phospho-ERK1/2. In addition, specific knockdown of MKP-1 with siRNA suppressed the downregulation of phospho-ERK1/2 and the reduction of proliferation induced by DEX. Altogether, our results indicate that downregulation of phospho-ERK1/2 is associated with reduction in proliferation found in islets of early lactating mothers. This mechanism is probably mediated by GC-induced MKP-1 expression.

scholarly journals Maternal high-fat diet induces insulin resistance and deterioration of pancreatic β-cell function in adult offspring with sex differences in mice

2014 ◽  
Vol 306 (10) ◽  
pp. E1163-E1175 ◽  
Author(s):  
Hisashi Yokomizo ◽  
Toyoshi Inoguchi ◽  
Noriyuki Sonoda ◽  
Yuka Sakaki ◽  
Yasutaka Maeda ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Sex Differences ◽  
High Fat Diet ◽  
Cell Function ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Plasma Estradiol ◽  
Β Cell Function ◽  
Estradiol Levels

Intrauterine environment may influence the health of postnatal offspring. There have been many studies on the effects of maternal high-fat diet (HFD) on diabetes and glucose metabolism in offspring. Here, we investigated the effects in male and female offspring. C57/BL6J mice were bred and fed either control diet (CD) or HFD from conception to weaning, and offspring were fed CD or HFD from 6 to 20 wk. At 20 wk, maternal HFD induced glucose intolerance and insulin resistance in offspring. Additionally, liver triacylglycerol content, adipose tissue mass, and inflammation increased in maternal HFD. In contrast, extending previous observations, insulin secretion at glucose tolerance test, islet area, insulin content, and PDX-1 mRNA levels in isolated islets were lower in maternal HFD in males, whereas they were higher in females. Oxidative stress in islets increased in maternal HFD in males, whereas there were no differences in females. Plasma estradiol levels were lower in males than in females and decreased in offspring fed HFD and also decreased by maternal HFD, suggesting that females may be protected from insulin deficiency by inhibiting oxidative stress. In conclusion, maternal HFD induced insulin resistance and deterioration of pancreatic β-cell function, with marked sex differences in adult offspring accompanied by adipose tissue inflammation and liver steatosis. Additionally, our results demonstrate that potential mechanisms underlying sex differences in pancreatic β-cell function may be related partially to increases in oxidative stress in male islets and decreased plasma estradiol levels in males.

scholarly journals Transcriptional activation of CBFβ by CDK11p110 is necessary to promote osteosarcoma cell proliferation

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Yong Feng ◽  
Yunfei Liao ◽  
Jianming Zhang ◽  
Jacson Shen ◽  
Zengwu Shao ◽  
...  
Keyword(s):  
Chromatin Immunoprecipitation ◽  
Transcriptional Analysis ◽  
Luciferase Assay ◽  
Osteosarcoma Cell ◽  
Osteosarcoma Cells ◽  
Chromatin Immunoprecipitation Assay ◽  
Immunoprecipitation Assay ◽  
Gel Shift Assay ◽  
Gel Shift

Abstract Background Aberrant expression of cyclin-dependent protein kinases (CDK) is a hallmark of cancer. CDK11 plays a crucial role in cancer cell growth and proliferation. However, the molecular mechanisms of CDK11 and CDK11 transcriptionally regulated genes are largely unknown. Methods In this study, we performed a global transcriptional analysis using gene array technology to investigate the transcriptional role of CDK11 in osteosarcoma. The promoter luciferase assay, chromatin immunoprecipitation assay, and Gel Shift assay were used to identify direct transcriptional targets of CDK11. Clinical relevance and function of core-binding factor subunit beta (CBFβ) were further accessed in osteosarcoma. Results We identified a transcriptional role of protein-DNA interaction for CDK11p110, but not CDK11p58, in the regulation of CBFβ expression in osteosarcoma cells. The CBFβ promoter luciferase assay, chromatin immunoprecipitation assay, and Gel Shift assay confirmed that CBFβ is a direct transcriptional target of CDK11. High expression of CBFβ is associated with poor outcome in osteosarcoma patients. Expression of CBFβ contributes to the proliferation and metastatic behavior of osteosarcoma cells. Conclusions These data establish CBFβ as a mediator of CDK11p110 dependent oncogenesis and suggest that targeting the CDK11- CBFβ pathway may be a promising therapeutic strategy for osteosarcoma treatment. Graphical Abstract

scholarly journals The Constitutive Lack of α7 Nicotinic Receptor Leads to Metabolic Disorders in Mouse

Biomolecules ◽  
2020 ◽  
Vol 10 (7) ◽  
pp. 1057
Author(s):  
Blandine Gausserès ◽  
Junjun Liu ◽  
Ewout Foppen ◽  
Cécile Tourrel-Cuzin ◽  
Ana Rodriguez Sanchez-Archidona ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Glucose Homeostasis ◽  
Metabolic Disorders ◽  
Late Onset ◽  
Cell Mass ◽  
Chow Diet ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Α7 Nachr ◽  
Old Mice

Objective: Type 2 diabetes (T2D) occurs by deterioration in pancreatic β-cell function and/or progressive loss of pancreatic β-cell mass under the context of insulin resistance. α7 nicotinic acetylcholine receptor (nAChR) may contribute to insulin sensitivity but its role in the pathogenesis of T2D remains undefined. We investigated whether the systemic lack of α7 nAChR was sufficient to impair glucose homeostasis. Methods: We used an α7 nAChR knock-out (α7−/−) mouse model fed a standard chow diet. The effects of the lack of α7 nAChR on islet mass, insulin secretion, glucose and insulin tolerance, body composition, and food behaviour were assessed in vivo and ex vivo experiments. Results: Young α7−/− mice display a chronic mild high glycemia combined with an impaired glucose tolerance and a marked deficit in β-cell mass. In addition to these metabolic disorders, old mice developed adipose tissue inflammation, elevated plasma free fatty acid concentrations and presented glycolytic muscle insulin resistance in old mice. Finally, α7−/− mice, fed a chow diet, exhibited a late-onset excessive gain in body weight through increased fat mass associated with higher food intake. Conclusion: Our work highlights the important role of α7 nAChR in glucose homeostasis. The constitutive lack of α7 nAChR suggests a novel pathway influencing the pathogenesis of T2D.

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