Regulation of growth hormone expression by Delta-like protein 1 (Dlk1)

Ansell, Peter; Zhou, Yunli; Schjeide, Brit-Maren M.; Kerner, Alissa; Zhao, Jing Hua; Zhang, Xun; Klibanski, Anne

doi:10.1016/j.mce.2007.04.002

Cited by 36 publications

(33 citation statements)

References 53 publications

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“…Interestingly, we observed that LOI/LOH of H19DMR not only was associated with higher IGF2 levels, but significantly correlated with overexpression of MEST and NNAT, which play an important role in fetal development (20)(21)(22)(23). Similar findings were published by Kohda et al who described a correlation of LOI at the IGF2/H19 locus and the MEST locus in case of lung adenocarcinomas (23).…”

Section: ------------------------------------------------------------supporting

confidence: 90%

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Altered expression of imprinted genes in Wilms tumors

Hubertus

Lacher²,

Rottenkolber³

et al. 2011

Oncol Rep

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Abstract. Overexpression of insulin-like growth factor 2 (IGF2), an imprinted gene located on chromosome 11p15, has been reported as a characteristic feature in various embryonal tumors, including Wilms tumor (WT). Recent studies specified loss of imprinting (LOI) in a differential methylated region (DMR) of the IGF2/H19 cluster or loss of heterozygosity (LOH), respectively, uniparental disomy (UPD) being responsible for this overexpression. However, the role of other imprinted genes in the genesis of WT is still unknown. In the current study, we analyzed transcriptional activity of the imprinted genes IGF2, H19, NNAT, DLK1, RTL1, MEG3, and MEST as well as the methylation status of the DMR of the IGF2/H19 cluster in a panel of 32 WTs. Except for H19, we detected massive overexpression of all genes in the majority of WTs compared to normal renal tissue, which was most prominent for the paternally expressed genes IGF2, NNAT, and MEST. Alterations of the H19DMR were found in two-thirds of the WTs. Moreover, we have seen a strong correlation between the transcriptional activity of IGF2, NNAT and MEST and LOI/LOH of H19DMR, which was inverse for H19. Expression of DLK1, RTL1 and MEG3 does not correlate with LOI/LOH of H19DMR. Altogether, our findings suggest that over-expression of imprinted genes is common in WTs and correlates at least for some imprinted genes with LOI of H19DMR. Thus, it may be speculated that alterations of the DNA modification machinery drive erroneous setting of methylation marks in imprinting regions throughout the genome, which leads to the concomitant activation of imprinted genes in blastomagenesis.

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Section: ------------------------------------------------------------supporting

confidence: 90%

“…NNAT, IGF2, and MEST are involved in development and growth (20)(21)(22)(23), whereas the non-coding RNA of H19 and MEG3 exert regulatory function on the adjacent imprinting clusters (24,25). DLK1 and RTL1 are responsible for neuroendocrine differentiation and development of the placenta (15,20,21).…”

Section: Expression Of Imprinted Genes In Wilms Tumormentioning

confidence: 99%

Altered expression of imprinted genes in Wilms tumors

Hubertus

Lacher²,

Rottenkolber³

et al. 2011

Oncol Rep

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“…Several previous studies have implicated DLK1 in GH regulation (38)(39)(40)(41), and also conversely GH in the regulation of DLK1 (42)(43)(44). Notably, a recent study reported a reduction in GH secretion after Dlk1 deletion (40).…”

Section: Discussionmentioning

confidence: 95%

DLK1/PREF1 regulates nutrient metabolism and protects from steatosis

Charalambous

Rocha

Radford

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance Hepatosteatosis or nonalcoholic fatty liver disease (NAFLD) is an important health problem affecting approximately 20% of the population of the United States and is associated with cardiovascular risk factors such as insulin resistance and obesity. Using a Delta-like homologue (Dlk1) [also known as preadipocyte factor 1 (Pref1)] transgenic model, we identified a new player in the growth hormone (GH) signaling pathway that, when overexpressed, is protective against obesity and hepatosteatosis. Because the dosage of circulating DLK1 is naturally elevated in early life and during pregnancy, we believe that our transgenic model mimics endogenous mechanisms of DLK1-mediated GH signaling modulation that are used during periods of metabolic stress to protect from steatosis and alter fuel utilization in the whole organism.

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“…23 In vitro analysis showed that FA1 represses GH transcription and revealing a feedback regulatory loop to keep GH function precisely modulated. 14 Human obesity has been associated with decreased GH secretion and low levels of insulin growth factor-1, 24 in this sense, we should expect lower levels of FA1 in obesity. However, our findings showed that FA1 levels increase with obesity.…”

Section: Discussionmentioning

confidence: 99%

Human serum levels of fetal antigen 1 (FA1/Dlk1) increase with obesity, are negatively associated with insulin sensitivity and modulate inflammation in vitro

et al. 2008

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Objective: To investigate fetal antigen 1 (FA1) protein within the context of human obesity and its relation with insulin sensitivity. Subjects: Cross-sectional study that analyses circulating levels of FA1 in two selected human cohorts: n ¼ 127 men for the study of FA1 circulating levels in the context of obesity and insulin sensitivity (S i ); and n ¼ 61 severely obese women before and after bariatric surgery. The response in vitro to FA1 protein on human cell lines of monocytes, preadipocytes and mature adipocytes was studied. Measurements: Anthropometrical parameters: body mass index, waist-to-hip ratio, waist circumference, fat-free mass and fat mass. Clinical parameters: lipid profile (high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, total cholesterol, triglycerides), glycemic profile (fasting glucose, insulin, S i , HOMA-IR (Homeostasis Model Assessment of Insulin Resistance), cytokines (sIL-6), adipokines (adiponectin) and circulating soluble fractions of tumor necrosis factor-a receptors 1 and 2 (sTNFR1 and sTNFR2). Results: In the obesity study, levels of FA1 in serum were found to increase with obesity. The S i index was negatively dependent on FA1 levels. In severe obesity, serum levels of FA1 decreased 1.4-fold 6 months after bariatric surgery. In vitro assays with FA1 protein on human monocytes and adipocytes cell lines modified the expression of pro-inflammatory cytokines and adipokines (tumor necrosis factor-a (TNFa), monocyte chemoattractant protein-1 (MCP-1), IL-6 (interleukin-6) and adiponectin). Conclusion: FA1 serum levels were increased in obese subjects and might influence S i . The stimulatory effect of FA1 protein on pro-inflammatory cytokines on both immune and adipose cell types could contribute to worsening the inflammatory environment observed in obesity.

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Regulation of growth hormone expression by Delta-like protein 1 (Dlk1)

Cited by 36 publications

References 53 publications

Altered expression of imprinted genes in Wilms tumors

Altered expression of imprinted genes in Wilms tumors

DLK1/PREF1 regulates nutrient metabolism and protects from steatosis

Human serum levels of fetal antigen 1 (FA1/Dlk1) increase with obesity, are negatively associated with insulin sensitivity and modulate inflammation in vitro

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