Effect of retinoic acid on cell proliferation and differentiation as well as on lipid synthesis, lipoprotein secretion, and apolipoprotein biogenesis

2007 ◽  
Vol 293 (6) ◽  
pp. G1178-G1189 ◽  
Author(s):  
Emilie Grenier ◽  
Françoise Schwalm Maupas ◽  
Jean-François Beaulieu ◽  
Ernest Seidman ◽  
Edgard Delvin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Retinoic Acid ◽  
Cell Differentiation ◽  
Gene Transcription ◽  
Cyclin D3 ◽  
Dietary Vitamin ◽  
Peroxisome Proliferator ◽  
Active Metabolites ◽  
Proliferation And Differentiation ◽  
Lipoprotein Secretion

Dietary vitamin A and its active metabolites are essential nutrients for many functions as well as potent regulators of gene transcription and growth. Although the epithelium of the small intestine is characterized by rapid and constant renewal and enterocytes play a central role in the absorption and metabolism of alimentary retinol, very little is known about the function of retinoids in the human gastrointestinal epithelium and mechanisms by which programs engage the cell cycle are poorly understood. We have assessed the effects of 10 μM 9- and 13- cis-retinoic acid (RA) on proliferation and differentiation processes, lipid esterification, apolipoprotein (apo) biogenesis and lipoprotein secretion along with nuclear factor gene transcription. Treatment of Caco-2 cells with RA at different concentrations and incubation periods revealed the reduction of thymidine incorporation in 60% preconfluent or 100% confluent cells. Concomitantly, RA 1) modulated D-type cyclins by reducing the mitogen-sensitive cyclin D1 and upregulating cyclin D3 expressions and 2) caused a trend of increase in p38 MAPK, which triggers CDX2, a central protein in cell differentiation. RA remained without effect on lipoprotein output and apo synthesis, even for apo A-I that possesses RARE in its promoter. RA, in combination with 22-hydroxycholesterol, could induce apo A-I gene expression without any impact on apo A-I mass. Only the gene expression of peroxisome proliferator-activated receptor (PPAR)β, retinoic receptor (RAR)β, and RARγ was augmented and no alteration was noted in PPARα, PPARγ, liver X receptor (LXR)α, LXRβ, and retinoid X receptors. Taken together, these data highlight RA-induced cell differentiation via specific signaling without a significant impact on apo A-I synthesis.

MiRNA Transcription Is Regulated by the PML-RARα Oncoprotein in Acute Promyelocytic Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4197-4197
Author(s):  
Jeannet Nigten ◽  
Ruth Knops ◽  
Gorica Nikoloski ◽  
Theo M. de Witte ◽  
Bert A. van der Reijden ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Retinoic Acid ◽  
Cell Differentiation ◽  
Fusion Protein ◽  
Acute Promyelocytic Leukemia ◽  
Mirna Expression ◽  
Promyelocytic Leukemia ◽  
Mirna Genes ◽  
Before And After

Abstract The discovery of the microRNA (miRNA) molecules has led to new insights into the regulation of gene expression. They are able to bind specific mRNA sequences, and due to inhibition of translation or mRNA degradation, miRNAs cause downregulation of their target genes. To date, several hundreds of unique human miRNAs have been described. So far, for only few of them the target mRNAs have been experimentally confirmed. MiRNAs have been linked to several important biological processes as early stage development, cell growth, cell differentiation and apoptosis. In addition, impaired miRNA expression has been implicated in tumorigenesis. Leukemia is often associated with mutated transcription factors and, as a consequence, deregulated gene expression and impaired proliferation and differentiation. Acute Promyelocytic Leukemia (APL), is characterised by the expression of the mutated transcription factor PML-RARα, which may interfere with the normal function of the retinoic acid receptor α (RARα), a nuclear hormone receptor that acts as a ligand-dependent transcription factor. APL is uniquely sensitive to treatment with the RARα ligand, all-trans retinoic acid (ATRA), which results in the expression of genes that induce terminal granulocytic differentiation of the leukemic blasts. To investigate whether miRNA expression is regulated by ATRA in APL, we performed Taqman miRNA assays for 157 different mature miRNAs in the APL cell line NB4 before and after treatment with ATRA. We found that ATRA induced a more than 10 fold upregulation of 18 miRNAs and a more than 10 fold downregulation of 2 miRNAs. These expression patterns were confirmed in primary APL patient cells before and after treatment with ATRA. To study whether the miRNA expression pattern was dependent on the PML-RARα fusion protein, we used U937 cells stably transfected with a zinc-inducible PML-RARα expression cassette (U937PR9, a kind gift of Dr Pelicci). Upon ATRA treatment, we found that several miRNAs were only induced in the presence of PML-RARα, suggesting that PML-RARα is implicated in the expression of these miRNAs. To investigate whether the PML-RARα fusion protein binds to the endogenous miRNA genes chromatin immunoprecipitation assays were performed with PML-RARα transfected 293 cells. We demonstrated the presence of PML-RARα protein on the miRNA genes. This indicates that the oncoprotein PML-RARα directly influences the expression of these miRNAs. The function of the PML-RARα targeted miRNAs in APL cell differentiation is currently being studied using retroviral expression vectors.

scholarly journals Multiple cytochrome P-450 genes are concomitantly regulated by vitamin A under steady-state conditions and by retinoic acid during hepatic first-pass metabolism

2011 ◽  
Vol 43 (1) ◽  
pp. 57-67 ◽  
Author(s):  
A. Catharine Ross ◽  
Christopher J. Cifelli ◽  
Reza Zolfaghari ◽  
Nan-qian Li
Keyword(s):  
Gene Expression ◽  
Retinoic Acid ◽  
Steady State ◽  
Vitamin A ◽  
Dynamic Range ◽  
Dynamic Change ◽  
The Body ◽  
Retinol Binding Protein ◽  
Dietary Vitamin ◽  
Wide Range

Vitamin A (retinol) is an essential precursor for the production of retinoic acid (RA), which in turn is a major regulator of gene expression, affecting cell differentiation throughout the body. Understanding how vitamin A nutritional status, as well as therapeutic retinoid treatment, regulates the expression of retinoid homeostatic genes is important for improvement of dietary recommendations and therapeutic strategies using retinoids. This study investigated genes central to processes of retinoid uptake and storage, release to plasma, and oxidation in the liver of rats under steady-state conditions after different exposures to dietary vitamin A (deficient, marginal, adequate, and supplemented) and acutely after administration of a therapeutic dose of all- trans-RA. Over a very wide range of dietary vitamin A, lecithin:retinol acyltransferase (LRAT) as well as multiple cytochrome P-450s (CYP26A1, CYP26B1, and CYP2C22) differed by diet and were highly correlated with one another and with vitamin A status assessed by liver retinol concentration (all correlations, P < 0.05). After acute treatment with RA, the same genes were rapidly and concomitantly induced, preceding retinoic acid receptor (RAR)β, a classical direct target of RA. CYP26A1 mRNA exhibited the greatest dynamic range (change of log 26 in 3 h). Moreover, CYP26A1 increased more rapidly in the liver of RA-primed rats than naive rats, evidenced by increased CYP26A1 gene expression and increased conversion of [3H]RA to polar metabolites. By in situ hybridization, CYP26A1 mRNA was strongly regulated within hepatocytes, closely resembling retinol-binding protein (RBP)4 in location. Overall, whether RA is produced endogenously from retinol or administered exogenously, changes in retinoid homeostatic gene expression simultaneously favor both retinol esterification and RA oxidation, with CYP26A1 exhibiting the greatest dynamic change.

Mechanism of all trans-retinoic acid and glucocorticoid regulation of surfactant protein mRNA

1998 ◽  
Vol 274 (4) ◽  
pp. L560-L566 ◽  
Author(s):  
Thomas N. George ◽  
Olga L. Miakotina ◽  
Kelli L. Goss ◽  
Jeanne M. Snyder
Keyword(s):  
Gene Expression ◽  
Retinoic Acid ◽  
Gene Transcription ◽  
Mrna Stability ◽  
Half Life ◽  
Normal Function ◽  
Mrna Levels ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Mrna Half Life

The surfactant proteins (SPs) are required for the normal function of pulmonary surfactant, a lipoprotein substance that prevents alveolar collapse at end expiration. We characterized the effects of cortisol and all trans-retinoic acid (RA) on SP-A and SP-B gene expression in H441 cells, a human pulmonary adenocarcinoma cell line. Cortisol, at 10−6M, caused a significant inhibition of SP-A mRNA to levels that were 60–70% of controls and a five- to sixfold increase in the levels of SP-B mRNA. RA alone (10−6M) had no effect on SP-A mRNA levels and modestly reduced the inhibitory effect of cortisol. RA alone and the combination of cortisol and RA both significantly increased SP-B mRNA levels. RA had no effect on the rate of SP-A gene transcription or on SP-A mRNA stability. Cortisol alone and the combination of cortisol and RA significantly inhibited the rate of SP-A gene transcription but had no effect on SP-A mRNA half-life. RA at 10−6 M had no effect on the rate of SP-B gene transcription but prolonged SP-B mRNA half-life. Cortisol alone and the combination of cortisol and RA caused a significant increase in the rate of SP-B gene transcription and also caused a significant increase in SP-B mRNA stability. We conclude that RA has no effect on SP-A gene expression and increases SP-B mRNA levels by an effect on SP-B mRNA stability and not on the rate of SP-B gene transcription. In addition, the effects of the combination of RA and cortisol were generally similar to those of cortisol alone.

scholarly journals The Pal3 Promoter Sequence Is Critical for the Regulation of Human Renin Gene Transcription by Peroxisome Proliferator-Activated Receptor-γ

Endocrinology ◽  
2008 ◽  
Vol 149 (9) ◽  
pp. 4647-4657 ◽  
Author(s):  
Vladimir T. Todorov ◽  
Michael Desch ◽  
Thomas Schubert ◽  
Armin Kurtz
Keyword(s):  
Gene Expression ◽  
Gene Transcription ◽  
Promoter Activity ◽  
Peroxisome Proliferator ◽  
Response Element ◽  
Peroxisome Proliferator Activated Receptor ◽  
Human Renin ◽  
Pparγ Agonist ◽  
Renin Gene ◽  
Stimulation Of

We recently reported that human renin gene transcription is stimulated by the nuclear receptor peroxisome proliferator-activated receptor (PPAR)-γ in the renin-producing cell line Calu-6. The effect of PPARγ was mapped to two sequences in the renin promoter: a direct repeat hormone response element (HRE), which is related to the classical PPAR response element (PPRE) and a nonconsensus palindromic element with a 3-bp spacer (Pal3). We now find that PPARγ binds to the renin HRE. Neither the human renin HRE nor the consensus PPRE was sufficient to attain the maximal stimulation of renin promoter activity by the PPARγ agonist rosiglitazone. In contrast, the human renin Pal3 element mediates both the full PPARγ-dependent activation of transcription and the PPARγ-driven basal renin gene transcription. The human renin Pal3 sequence was found to selectively bind PPARγ and the retinoid X receptor-α from Calu-6 nuclear extracts. This is in contrast to the consensus PPRE, which can bind other nuclear proteins. PPARγ knockdown paradoxically did not attenuate the stimulation of the endogenous renin gene expression by rosiglitazone. Similarly, a deficiency of PPARγ did not attenuate the activation of the minimal human renin promoter, which contains the endogenous Pal3 motif. However, when the human renin Pal3 site was replaced by the consensus PPRE sequence, PPARγ knockdown abrogated the effect of rosiglitazone on renin promoter activity. Thus, the human renin Pal3 site appears to be critical for the PPARγ-dependent regulation of gene expression by mediating maximal transcription activation, particularly at the low cellular level of PPARγ.

scholarly journals Sp1 up-regulates cAMP-response-element-binding protein expression during retinoic acid-induced mucous differentiation of normal human bronchial epithelial cells

2008 ◽  
Vol 410 (1) ◽  
pp. 49-61 ◽  
Author(s):  
Jeong Soo Hong ◽  
Seung-Wook Kim ◽  
Ja Seok Koo
Keyword(s):  
Gene Expression ◽  
Retinoic Acid ◽  
Cell Differentiation ◽  
Epithelial Cells ◽  
Camp Response Element Binding ◽  
Camp Response Element ◽  
Response Element ◽  
Bronchial Epithelial ◽  
Element Binding Protein ◽  
Normal Human

CREB [CRE (cAMP-response element)-binding protein] is an important transcription factor that is differentially regulated in cells of various types. We recently reported that RA (retinoic acid) rapidly activates CREB without using RARs (RA receptors) or RXRs (retinoid X receptors) in NHTBE cells (normal human tracheobronchial epithelial cells). However, little is known about the role of RA in the physiological regulation of CREB expression in the early mucous differentiation of NHTBE cells. In the present study, we report that RA up-regulates CREB gene expression and that, using 5′-serial deletion promoter analysis and mutagenesis analyses, two Sp1 (specificity protein 1)-binding sites located at nt −217 and −150, which flank the transcription initiation site, are essential for RA induction of CREB gene transcription. Furthermore, we found that CREs located at nt −119 and −98 contributed to basal promoter activity. Interestingly, RA also up-regulated Sp1 in a time- and dose-dependent manner. Knockdown of endogenous Sp1 using siRNA (small interfering RNA) decreased RA-induced CREB gene expression. However, the converse was not true: knockdown of CREB using CREB siRNA did not affect RA-induced Sp1 gene expression. We conclude that RA up-regulates CREB gene expression during the early stage of NHTBE cell differentiation and that RA-inducible Sp1 plays a major role in up-regulating human CREB gene expression. This result implies that co-operation of these two transcription factors plays a crucial role in mediating early events of normal mucous cell differentiation of bronchial epithelial cells.

scholarly journals Transcription Suppression of Peroxisome Proliferator-Activated Receptor γ2 Gene Expression by Tumor Necrosis Factor α via an Inhibition of CCAAT/ Enhancer-binding Protein δ during the Early Stage of Adipocyte Differentiation

Endocrinology ◽  
2004 ◽  
Vol 145 (11) ◽  
pp. 4948-4956 ◽  
Author(s):  
Masataka Kudo ◽  
Akira Sugawara ◽  
Akira Uruno ◽  
Kazuhisa Takeuchi ◽  
Sadayoshi Ito
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Gene Transcription ◽  
Adipocyte Differentiation ◽  
Early Stage ◽  
Binding Protein ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Protein Levels ◽  
Enhancer Binding Protein

Abstract TNFα is known to inhibit adipocyte differentiation and induce insulin resistance. Moreover, TNFα is known to down-regulate peroxisome proliferator-activated receptor (PPAR)γ2, an adipocyte-specific nuclear receptor of insulin-sensitizer thiazolidinediones. To clarify molecular mechanisms of TNFα- mediated PPARγ2 down-regulation, we here examined the effect of TNFα on transcription regulation of PPARγ2 gene expression during the early stage of adipocyte differentiation. 3T3-L1 preadipocytes (2 d after 100% confluent) were incubated in a differentiation mixture (dexamethasone, insulin, 3-isobutyl-1-methlxanthine), with or without 50 ng/ml TNFα, for 24 h. TNFα significantly decreased PPARγ2 expression both at mRNA and protein levels (to ∼40%), as well as aP2 mRNA expression. The mouse PPARγ2 gene promoter region (2.2-kb) was isolated and was used for luciferase reporter assays by transient transfection. TNFα significantly suppressed PPARγ2 gene transcription (to ∼50%), and deletion analyses demonstrated that the suppression was mediated via CCAAT/enhancer-binding protein (C/EBP) binding elements at the −320/−340 region of the promoter. Moreover, TNFα significantly decreased expression of C/EBPδ mRNA and protein levels (to ∼40%). EMSA, using 3T3-L1 cells nuclear extracts with the −320/−340 region as a probe, demonstrated the binding of C/EBPδ to the element, which was significantly decreased by TNFα treatment. Overexpression of CEBP/δ prevented the TNFα-mediated suppression of PPARγ2 transactivation. Taken together, TNFα suppresses PPARγ2 gene transcription by the inhibition of C/EBPδ expression and its DNA binding during the early stage of adipocyte differentiation, which may contribute to the inhibition of adipocyte differentiation, as well as the induction of insulin resistance.

scholarly journals PPARγ controls CD1d expression by turning on retinoic acid synthesis in developing human dendritic cells

2006 ◽  
Vol 203 (10) ◽  
pp. 2351-2362 ◽  
Author(s):  
Istvan Szatmari ◽  
Attila Pap ◽  
Ralph Rühl ◽  
Jiang-Xing Ma ◽  
Petr A. Illarionov ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dendritic Cells ◽  
Retinoic Acid ◽  
Antigen Presentation ◽  
Cell Activation ◽  
Acid Synthesis ◽  
Inkt Cell ◽  
Peroxisome Proliferator ◽  
Lipid Antigen

Dendritic cells (DCs) expressing CD1d, a molecule responsible for lipid antigen presentation, are capable of enhancing natural killer T (iNKT) cell proliferation. The signals controlling CD1 expression and lipid antigen presentation are poorly defined. We have shown previously that stimulation of the lipid-activated transcription factor, peroxisome proliferator-activated receptor (PPAR)γ, indirectly regulates CD1d expression. Here we demonstrate that PPARγ, turns on retinoic acid synthesis by inducing the expression of retinol and retinal metabolizing enzymes such as retinol dehydrogenase 10 and retinaldehyde dehydrogenase type 2 (RALDH2). PPARγ-regulated expression of these enzymes leads to an increase in the intracellular generation of all-trans retinoic acid (ATRA) from retinol. ATRA regulates gene expression via the activation of the retinoic acid receptor (RAR)α in human DCs, and RARα acutely regulates CD1d expression. The retinoic acid–induced elevated expression of CD1d is coupled to enhanced iNKT cell activation. Furthermore, in vivo relevant lipids such as oxidized low-density lipoprotein can also elicit retinoid signaling leading to CD1d up-regulation. These data show that regulation of retinoid metabolism and signaling is part of the PPARγ-controlled transcriptional events in DCs. The uncovered mechanisms allow the DCs to respond to altered lipid homeostasis by changing CD1 gene expression.

scholarly journals 249BOVINE GRANULOSA CELLS MRNA EXPRESSION OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-± AND THE PROTO-ONCOGENE C-FOS

2004 ◽  
Vol 16 (2) ◽  
pp. 245 ◽  
Author(s):  
A. Rodriguez ◽  
L.J. Royo ◽  
F. Goyache ◽  
C. Diez ◽  
E. Moran ◽  
...  
Keyword(s):  
Gene Expression ◽  
Retinoic Acid ◽  
Mrna Expression ◽  
Granulosa Cells ◽  
Hormone Receptor ◽  
Peroxisome Proliferator ◽  
Cdna Synthesis ◽  
Peroxisome Proliferator Activated Receptor ◽  
Positive Controls ◽  
Whole Ovary

PPARα and c-Fos are involved in regulation of gene expression and are known to be dependent on retinoic acid (RA), which in turn influences oocyte growth and developmental competence (Duque et al., 2002 Hum. Reprod. 17, 2706–2714; Hidalgo et al., 2003. Reproduction 125, 409–416), probably acting in part through granulosa cells. Peroxisome proliferator-activated receptor-α (PPARα) heterodimerizes with the retinoid receptor X (RXR), while c-Jun/c-Fos heterodimerizes with liganded retinoic acid receptors (RARs), then preventing formation of transcription factor activator protein 1 (AP-1) complexes capable of DNA binding. Cellular retinoic acid binding protein (CRABP) limits RA excess and regulates the transcriptional potential of RA;; CRABPII has been detected in rat granulosa cells from mature follicles and luteal cells. The aim of this study was to investigate PPARα, c-Fos and CRABPII mRNA expression in bovine granulosa cells. In parallel, other genes whose expression can be influenced by RA were analyzed: luteinizing hormone receptor (LHr), follicle stimulating hormone receptor (FSHr), aromatase and growth hormone (GH). Ovaries were collected at a local abattoir and kept in saline at 30–35°C. Granulosa cells were obtained by aspirating 2- to 7-mm antral follicle contents, pelleted at 700g for 4min and resuspended in RNA-later (Ambion®). Total RNA was isolated with a NucleoSpin® RNAII kit (Macherey-Nagel), and mRNA was reverse transcribed into single-stranded cDNA using a 1st Strand cDNA Synthesis Kit for RT-PCR (AMV) (Roche). A PCR standard method was made using 1μL of the cDNA as a template. All PCR primer couples were designed on the basis of the bovine sequence, but c-Fos and CRABPII primers were designed based on the human-murine sequences. Primers within the couple were located in different exons to distinguish DNA from RNA amplification. CRABPII was further investigated in bovine whole ovary, corpus luteum (CL) and liver, in a search for positive controls. Bovine β-actin, 18S and 28S were examined in each sample as positive controls for RNA isolation and cDNA synthesis efficiency. TenμL of product were loaded into an agarose 2% gel in TBE buffer containing ethidium bromide, and were separated by horizontal electrophoresis. Gels were visualized with ultraviolet light and photographed using a digital camera. Gene expression in granulosa was demonstrated for PPARα, c-Fos, LHr, FSHr, aromatase, GH and controls (β-actin, 18S and 28S) but CRABPII gene did not express in granulosa cells, whole ovary, CL or liver under our experimental conditions. While lacking CRABPII expression remains intriguing, the expressed genes support a role of retinoid pathway within granulosa cells under both in vivo and in vitro conditions, because granulosa cells used in the present experiments were derived from follicles providing oocytes for IVM-IVF. Grant support: Spanish Ministry of Science and Technology (AGL-2002-01175).

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