scholarly journals Retinoic Acid Receptor γ1 (RARγ1) Levels Control RARβ2 Expression in SK-N-BE2(c) Neuroblastoma Cells and Regulate a Differentiation-Apoptosis Switch

1998 ◽  
Vol 18 (11) ◽  
pp. 6482-6492 ◽  
Author(s):  
Nicoletta Ferrari ◽  
Magnus Pfahl ◽  
Giovanni Levi
Keyword(s):  
Retinoic Acid ◽  
Morphological Changes ◽  
Retinoic Acid Receptor ◽  
Neuroblastoma Cells ◽  
Constitutive Expression ◽  
Cell Types ◽  
Regulation Of Expression ◽  
Reciprocal Regulation ◽  
Regulatory Processes ◽  
Spatio Temporal

ABSTRACT Vitamin A and its derivatives (retinoids) have profound effects on the proliferation and differentiation of many cell types and are involved in a diverse array of developmental and physiological regulatory processes, including those responsible for the development of the mature nervous system. Retinoid signals are mediated by retinoic acid (RA) receptors (RARs) and retinoid X receptors (RXRs), which show distinct spatio-temporal patterns of expression during development and in adult tissues. We have used SK-N-BE2(c) neuroblastoma cells to study the effects of reciprocal regulation of expression of various RARs. We show that in these cells RARγ1 acts as a repressor of RARβ2 transcription in the absence of an agonist. In the presence of RA, the expression of RARγ1 is reduced and that of RARβ2 is induced. Overexpression of RARγ1 neutralizes the effects of RA on RARβ induction. Expression of an RARγ1-specific antisense construct leads to the constitutive expression of RARβ2. Although both overexpression of RARγ1 and its reduction of expression can result in inhibition of cell proliferation, they induce different morphological changes. Reduction of RARγ1 (and induction of RARβ) leads to increased apoptosis, whereas RARγ1 overexpression leads to differentiation in the absence of apoptosis. Thus, RARγ1 appears to control a differentiation-apoptosis switch in SK-N-BE2(c) neuroblastoma cells.

Rapid and transient decrease of N-myc expression in retinoic acid-induced differentiation of OTF9 teratocarcinoma stem cells

1990 ◽  
Vol 10 (2) ◽  
pp. 486-491
Author(s):  
K Kato ◽  
A Kanamori ◽  
H Kondoh
Keyword(s):  
Stem Cells ◽  
Retinoic Acid ◽  
Morphological Changes ◽  
Constitutive Expression ◽  
Stem Cell Line ◽  
Induced Differentiation ◽  
Transient Decrease ◽  
Mouse Teratocarcinoma ◽  
Very High

The level of expression of N-myc in mouse teratocarcinoma stem cells is very high. Previous studies have shown that N-myc expression significantly decreases when the stem cells are subjected to long-term induction for differentiation by retinoic acid (RA). We found that in a stem cell line, OTF9, a steep yet transient decrease of N-myc expression takes place much earlier, immediately after induction by RA. To examine whether this decrease is responsible for differentiation, we constructed a gene, miwNmyc, to express N-myc cDNA constitutively and transformed OTF9 cells with this gene construct. Transformants under the constitutive expression of miwNmyc differentiated normally, as judged by morphological changes and by modulation of c-myc, Hox1.1, and laminin B1 expression. Therefore, transient decrease of N-myc expression may be the consequence of RA-induced differentiation, even though it occurs very early in the process. Alternatively, in addition to N-myc decrease, there may be redundant mechanisms which lead to OTF9 differentiation after induction by RA, so that suppression of N-myc decrease is bypassed by at least one other mechanism.

Expression of ATRA Inducible RARα2 Isoform Is Deregulated in AML.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1204-1204
Author(s):  
Annegret Glasow ◽  
Angela Barrett ◽  
Rajeev Gupta ◽  
David Grimwade ◽  
Marieke von Lindern ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Retinoic Acid ◽  
Cell Lines ◽  
Histone Deacetylases ◽  
Target Genes ◽  
Retinoic Acid Receptor ◽  
Cell Types ◽  
Dna Methyltransferases ◽  
Protein Isoforms ◽  
Epigenetic Changes

Abstract Retinoids exert a variety of effects on both normal and malignant hematopoietic cells. To date, three different retinoic acid receptor (RAR) and retinoid X receptor (RXR) genes have been characterized, each encoding multiple N-terminal protein isoforms. RXRs serve as co-regulators for RARs, and many other nuclear receptors integrating different signalling pathways. All-trans-retinoic acid (ATRA) signaling pathway is of critical importance for optimal myelomonocytic differentiation and its disruption by translocations of the RARα gene leads to acute promyelocytic leukemia (APL). APL associated fusion oncoproteins, such as PML-RARα and PLZF-RARα, function through recruitment of histone deacetylases (HDACs) and DNA methyltransferases (DNMTs), thus promoting an inactive chromatin state and leading to repression of RARα target genes. Recently, we demonstrated that up-regulation of RARα2 expression by ATRA directly correlates with differentiation of APL and non-APL AML cells and that RARα2 transcription is silenced by DNA methylation in AML cell lines. Using primary AML samples as well as normal cord and peripheral blood derived cells representing different stages of myelomonocytic development we now show that expression of RARα2 increases with maturation of hematopietic cells. Expression of RARα1 on the other hand, which is transcribed from a distinct promoter, remains relatively constant throughout the different stages of myelomonocytic development. The levels of RARα1 expression in various primary AML cell types appear to be similar to those found in normal hematopietic cells. Consistent with data derived from AML cell lines, however, the RARα2 isoform is poorly expressed in all samples. Compared with CD34+/CD133+ or CD34+ progenitors, and more mature CD33+ myeloid cells, RARα2 is expressed at much lower levels in a variety of primary AML cells and its expression is not effectively induced by myelomonocytic growth factors and/or ATRA. Negatively acting epigenetic changes, such as DNA methylation, appear to be responsible for deregulated expression of RARα2 in AML cells, although their pattern and extent differs significantly between AML cell lines and primary AML samples. Taken together our data suggest that agents, which revert negatively acting epigenetic changes may restore expression of the RARα2 isoform in AML cells and render them more responsive to ATRA as well as other differentiation inducers.

scholarly journals Rapid and transient decrease of N-myc expression in retinoic acid-induced differentiation of OTF9 teratocarcinoma stem cells.

1990 ◽  
Vol 10 (2) ◽  
pp. 486-491 ◽  
Author(s):  
K Kato ◽  
A Kanamori ◽  
H Kondoh
Keyword(s):  
Stem Cells ◽  
Retinoic Acid ◽  
Morphological Changes ◽  
Constitutive Expression ◽  
Stem Cell Line ◽  
Induced Differentiation ◽  
Transient Decrease ◽  
Mouse Teratocarcinoma ◽  
Very High

The level of expression of N-myc in mouse teratocarcinoma stem cells is very high. Previous studies have shown that N-myc expression significantly decreases when the stem cells are subjected to long-term induction for differentiation by retinoic acid (RA). We found that in a stem cell line, OTF9, a steep yet transient decrease of N-myc expression takes place much earlier, immediately after induction by RA. To examine whether this decrease is responsible for differentiation, we constructed a gene, miwNmyc, to express N-myc cDNA constitutively and transformed OTF9 cells with this gene construct. Transformants under the constitutive expression of miwNmyc differentiated normally, as judged by morphological changes and by modulation of c-myc, Hox1.1, and laminin B1 expression. Therefore, transient decrease of N-myc expression may be the consequence of RA-induced differentiation, even though it occurs very early in the process. Alternatively, in addition to N-myc decrease, there may be redundant mechanisms which lead to OTF9 differentiation after induction by RA, so that suppression of N-myc decrease is bypassed by at least one other mechanism.

scholarly journals Histone Deacetylase Inhibitors Regulate Retinoic Acid Receptor β Expression in Neuroblastoma Cells by Both Transcriptional and Posttranscriptional Mechanisms

2007 ◽  
Vol 21 (10) ◽  
pp. 2416-2426 ◽  
Author(s):  
Maxy De los Santos ◽  
Alberto Zambrano ◽  
Aurora Sánchez-Pacheco ◽  
Ana Aranda
Keyword(s):  
Retinoic Acid ◽  
Tumor Suppressor ◽  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Retinoic Acid Receptor ◽  
Neuroblastoma Cells ◽  
Prolonged Treatment ◽  
Mrna Levels ◽  
Human Neuroblastoma ◽  
Acid Receptor

Abstract The retinoic acid receptor β (RARβ) is a retinoic acid (RA)-inducible tumor suppressor, which plays an important role in the arrest of neuroblastoma cell growth. Using human neuroblastoma SH-SY5Y cells, we have examined the regulation of RARβ expression by histone deacetylase inhibitors (HDACi), considered to be promising agents in anticancer therapy. Our results show that HDACi cooperated with RA to increase RARβ mRNA levels and to activate the RARβ2 promoter in transient transfection assays. Chromatin immunoprecipitation assays showed that the basal RARβ2 promoter that contains the RA response element was refractory to acetylation by both HDACi and RA. In addition, HDACi caused a transient increase in acetylation of a downstream RARβ2 region, even though global histones remain hyperacetylated after a prolonged treatment with the inhibitors. RA potentiated this response and maintained acetylation for a longer period. Despite the cooperation of RA with HDACi to increase transcription of the RARβ gene, these inhibitors caused a paradoxical reduction of the cellular levels of the RARβ protein in cells treated with the retinoid. This reduction is secondary to a change in the protein half-life that is decreased by the HDACi due to increased ubiquitin-independent proteasomal degradation. These results show that HDACi regulate expression of the tumor suppressor gene RARβ by both transcriptional and posttranscriptional mechanisms and might then modulate sensitivity to the retinoid in neuroblastoma cells.

Genomic and proteomic analysis of the myeloid differentiation program

Blood ◽  
2001 ◽  
Vol 98 (3) ◽  
pp. 513-524 ◽  
Author(s):  
Zheng Lian ◽  
Le Wang ◽  
Shigeru Yamaga ◽  
Wesley Bonds ◽  
Y. Beazer-Barclay ◽  
...  
Keyword(s):  
Gene Expression ◽  
Retinoic Acid ◽  
Bone Marrow Cells ◽  
Retinoic Acid Receptor ◽  
Expression Patterns ◽  
Cell Types ◽  
Dominant Negative ◽  
Myeloid Differentiation ◽  
Mrna Levels ◽  
Murine Bone Marrow

Abstract Although the mature neutrophil is one of the better characterized mammalian cell types, the mechanisms of myeloid differentiation are incompletely understood at the molecular level. A mouse promyelocytic cell line (MPRO), derived from murine bone marrow cells and arrested developmentally by a dominant-negative retinoic acid receptor, morphologically differentiates to mature neutrophils in the presence of 10 μM retinoic acid. An extensive catalog was prepared of the gene expression changes that occur during morphologic maturation. To do this, 3′-end differential display, oligonucleotide chip array hybridization, and 2-dimensional protein electrophoresis were used. A large number of genes whose mRNA levels are modulated during differentiation of MPRO cells were identified. The results suggest the involvement of several transcription regulatory factors not previously implicated in this process, but they also emphasize the importance of events other than the production of new transcription factors. Furthermore, gene expression patterns were compared at the level of mRNA and protein, and the correlation between 2 parameters was studied.

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