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Institute for Health and Sport (iHeS), Victoria University, Melbourne, Victoria, Australia
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Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
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Protein kinase D (PKD) is emerging as an important kinase regulating energy balance and glucose metabolism; however, whether hepatic PKD activity can be targeted to regulate these processes is currently unclear. In this study, hepatic PKD activity was reduced using adeno-associated virus vectors to express a dominant-negative (DN) version of PKD1, which impairs the action of all three PKD isoforms. In chow-fed mice, hepatic DN PKD expression increased whole-body glucose oxidation, but had only mild effects on glucose and insulin tolerance and no effects on glucose homeostasis following fasting and refeeding. However, circulating VLDL cholesterol was reduced under these conditions and was associated with hepatic fatty acid accumulation, but not lipids involved in lipoprotein synthesis. The limited effects on glucose homeostasis in DN PKD mice was despite reduced expression of gluconeogenic genes under both fasted and refed conditions, and enhanced pyruvate tolerance. The requirement for PKD for gluconeogenic capacity was supported by in vitro studies in cultured FAO hepatoma cells expressing DN PKD, which produced less glucose under basal conditions. Although these pathways are increased in obesity, the expression of DN PKD in the liver of mice fed a high-fat diet had no impact on glucose tolerance, insulin action, pyruvate tolerance or plasma VLDL. Together, these data suggest that PKD signalling in the liver regulates metabolic pathways involved in substrate redistribution under conditions of normal nutrient availability, but not under conditions of overnutrition such as in obesity.
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Department of Basic Medical Sciences, School of Mathematical and Natural Sciences, University of Arizona College of Medicine, 425 North 5th Street, Phoenix, Arizona 85004-2157, USA
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Department of Basic Medical Sciences, School of Mathematical and Natural Sciences, University of Arizona College of Medicine, 425 North 5th Street, Phoenix, Arizona 85004-2157, USA
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The vitamin D receptor (VDR), but not its hormonal ligand, 1,25-dihydroxyvitamin D3 (1,25D), is required for the progression of the mammalian hair cycle. We studied three genes relevant to hair cycle signaling, DKKL1 (Soggy), SOSTDC1 (Wise), and HR (Hairless), to determine whether their expression is regulated by VDR and/or its 1,25D ligand. DKKL1 mRNA was repressed 49–72% by 1,25D in primary human and CCD-1106 KERTr keratinocytes; a functional vitamin D responsive element (VDRE) was identified at −9590 bp in murine Soggy. Similarly, SOSTDC1 mRNA was repressed 41–59% by 1,25D in KERTr and primary human keratinocytes; a functional VDRE was located at −6215 bp in human Wise. In contrast, HR mRNA was upregulated 1.56- to 2.77-fold by 1,25D in primary human and KERTr keratinocytes; a VDRE (TGGTGAgtgAGGACA) consisting of an imperfect direct repeat separated by three nucleotides (DR3) was identified at −7269 bp in the human Hairless gene that mediated dramatic induction, even in the absence of 1,25D ligand. In parallel, a DR4 thyroid hormone responsive element, TGGTGAggccAGGACA, was identified at +1304 bp in the human HR gene that conferred tri-iodothyronine (T3)-independent transcriptional activation. Because the thyroid hormone receptor controls HR expression in the CNS, whereas VDR functions in concert with the HR corepressor specifically in skin, a model is proposed wherein unliganded VDR upregulates the expression of HR, the gene product of which acts as a downstream comodulator to feedback-repress DKKL1 and SOSTDC1, resulting in integration of bone morphogenic protein and Wnt signaling to drive the mammalian hair cycle and/or influencing epidermal function.
School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, UK
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School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, UK
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School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, UK
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School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, UK
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School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, UK
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-cell function. Genes altered by l -glutamine addition were grouped as follows: signal transduction (16%), growth/gene regulation (16%), metabolism (10%), structural (7%) channels/receptors (6%), apoptosis/inflammatory response (4%), transport (2
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Department of Minimally Invasive Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
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Department of Nutrition, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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KIIT School of Biotechnology, KIIT University, Bhubaneswar, India
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, these thermogenic changes proceed without upregulation of Prdm16 . Similar gene regulation, involved in thermogenic response and mitochondrial oxidation, was found in rats treated with Lep -expressing adenovirus ( Zhou et al . 1999 ). Cao and co
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been made in understanding transcriptional gene regulation during follicular and luteal development ( Wu & Wiltbank 2002 , Liu et al . 2009 , Patel et al . 2009 , Pisarska et al . 2011 ), little is known about the post-transcriptional mechanisms
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Expression of a gene can be controlled at many levels, including transcription, mRNA splicing, mRNA stability, translation and post-translational events such as protein stability and modification. The majority of studies to date have focused on transcriptional control mechanisms, but the importance of post-transcriptional mechanisms in regulating gene expression in eukaryotes is becoming increasingly clear. In this short review, selected examples of post-transcriptional gene regulatory mechanisms operating in both lower and higher eukaryotes will be used to highlight the plethora of such mechanisms already identified. The underlying theme is that post-transcriptional gene regulation relies on specific RNA-protein interactions that either result in the targeted degradation of the mRNA or prevent access of the ribosome to the translation start codon. Such interactions can occur in the 5' or 3' untranslated regions of an mRNA or within the decoded portion of the molecule. The importance of these regulatory mechanisms in a range of biological systems is also illustrated.
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The insulin receptor-related receptor (IRR), a member of the insulin receptor tyrosine kinase family, has structural homology to the insulin receptor (IR) and the IGF-I receptor (IGF-IR). The ligand, gene regulation and biological function of the IRR are not known. Because mRNAs for both the IR and IGF-IR are increased by nutrient restriction, we used RNase protection assays to assess the effects of fasting 48 h on IRR mRNA in kidneys of rats. We compared the changes in IRR with those in IR and IGF-IR mRNAs. We observed a significant increase in steady state levels of IRR (ratio of IRR mRNA to beta-actin in fed P<0.01), suggesting that the ligand for IRR also might be regulated by nutrients.
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Although analysis of luciferase activity using luminescence imaging has provided new insights into the dynamic regulation of gene expression in living tIssues, studies in vitro have relied on stably transfected clonal cell lines, limiting the choice of cell type and species, or DNA microinjection, which is arduous and highly selective. We report here the first use of a recombinant adenovirus in which the firefly luciferase reporter gene was regulated by the prolactin gene promoter, to study temporal dynamics of promoter activity. This vector was used to infect the pituitary GH3 cell line, and also primary cultures of Syrian hamster pituitary cells. We show that adenovirally transduced cells retained normal regulation of the promoter-reporter transgene by appropriate signals. Furthermore, microscopic imaging studies indicated that both clonal and primary pituitary cells were transduced efficiently, giving readily detectable luminescence signals in real-time over long periods. Finally, analysis of single-cell expression patterns indicated that prolactin promoter activity was highly dynamic with pulses in gene expression, revealing that the transcriptional instability seen in clonal cells is a feature of normal pituitary cells. Adenoviral vectors offer a valuable tool for studies of gene regulation where conventional transgenesis and clonal cell lines are not available.
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Bioactive peptides derived from the prohormone, pro-opiomelanocortin (POMC), are generated in neurons of the hypothalamus and act as endogenous ligands for the melanocortin-4 receptor (MC4R), a key molecule underlying appetite control and energy homeostasis. It is therefore important to understand many aspects of POMC gene regulation in the brain, as pharmacological manipulation of POMC expression/processing could be a potential strategy to combat obesity. Most studies that have analysed POMC gene expression in the hypothalamus have focused on gene transcription experiments. Ultimately, however, factors that regulate post-translational processing and secretion of peptides will have most bearing on melanocortin signalling. This article focuses on (a) current evidence that POMC is involved in obesity, (b) how POMC transcription is regulated in the hypothalamus, (c) the mechanism by which proteolytic processing of POMC is controlled in the hypothalamus and what peptides are produced and (d) which POMC-derived peptides are the most potent ligands at the melanocortin receptor in vitro and in vivo. It seems that post-translational cleavage of POMC in the hypothalamus may be regulated with respect to energy requirement. We predict that further research into hypothalamic POMC processing, and the proteolytic enzymes involved, may yield important new clues on how flux through the MC4R pathway is regulated.
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More than a decade ago our view of gene regulation by glucocorticoids (GC) and other steroid hormones underwent a dramatic change with the discovery of negative crosstalk (transcriptional interference) between the GC receptor (GCR) and transcription factor AP-1 (Jun:Fos). It was initially observed that induction of the collagenase type 1 gene, which is mediated through activation of AP-1 by growth factors and inflammatory cytokines, is repressed by GC. This repression was attributed to mutual negative interactions between AP-1 and GCR. Although the exact molecular mechanism underlying this particular case of transcriptional interference is yet to be determined, it has become clear that this and analogous interactions with other transcription factors (e.g. nuclear factor-kappaB) underlie the anti-inflammatory and immunosuppressive activity of GC. Recent studies conducted at the whole animal level indicate that the interactions between the AP-1 and GC signaling pathways are much more extensive. AP-1-related signaling via the Jun N-terminal kinases can lead to increased levels of circulating GC, which eventually down-modulate AP-1 activity via transcriptional interference. This negative feedback loop is likely to be of great importance for maintenance of homeostasis and regulation of stress responses, including acute and chronic inflammation.
