scholarly journals Targeted disruption of retinoic acid receptor alpha (RAR alpha) and RAR gamma results in receptor-specific alterations in retinoic acid-mediated differentiation and retinoic acid metabolism.

1995 ◽  
Vol 15 (2) ◽  
pp. 843-851 ◽  
Author(s):  
J F Boylan ◽  
T Lufkin ◽  
C C Achkar ◽  
R Taneja ◽  
P Chambon ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Retinoic Acid Receptor ◽  
Specific Gene ◽  
Cell Type ◽  
Targeted Disruption ◽  
F9 Cells ◽  
Retinoid Receptors ◽  
Alpha Gene ◽  
Polar Derivatives ◽  
Crabp Ii

F9 embryonic teratocarcinoma stem cells differentiate into an epithelial cell type called extraembryonic endoderm when treated with retinoic acid (RA), a derivative of retinol (vitamin A). This differentiation is presumably mediated through the actions of retinoid receptors, the RARs and RXRs. To delineate the functions of each of the different retinoid receptors in this model system, we have generated F9 cell lines in which both copies of either the RAR alpha gene or the RAR gamma gene are disrupted by homologous recombination. The absence of RAR alpha is associated with a reduction in the RA-induced expression of both the CRABP-II and Hoxb-1 (formerly 2.9) genes. The absence of RAR gamma is associated with a loss of the RA-inducible expression of the Hoxa-1 (formerly Hox-1.6), Hoxa-3 (formerly Hox-1.5), laminin B1, collagen IV (alpha 1), GATA-4, and BMP-2 genes. Furthermore, the loss of RAR gamma is associated with a reduction in the metabolism of all-trans-RA to more polar derivatives, while the loss of RAR alpha is associated with an increase in metabolism of RA relative to wild-type F9 cells. Thus, each of these RARs exhibits some specificity with respect to the regulation of differentiation-specific gene expression. These results provide an explanation for the expression of multiple RAR types within one cell type and suggest that each RAR has specific functions.

scholarly journals Tissue-specific distribution of a novel C-terminal truncation retinoic acid receptor mutant which acts as a negative repressor in a promoter- and cell-type-specific manner.

1995 ◽  
Vol 15 (4) ◽  
pp. 1961-1967 ◽  
Author(s):  
T Matsui ◽  
S Sashihara
Keyword(s):  
Retinoic Acid ◽  
Retinoic Acid Receptor ◽  
Cell Type ◽  
F9 Cells ◽  
Acid Receptor ◽  
Retinoic Acid Response Element ◽  
Specific Distribution ◽  
Mouse Tissues ◽  
Specific Manner ◽  
Cell Type Specific

A cDNA clone which encodes a truncation form of the gamma subtype of the retinoic acid receptor (RAR gamma) has been isolated. The mutant RAR gamma (RAR gamma Bm382) has lost its 65 C-terminal amino acids, thus truncating a part of the dimerization and activation domains. By using a reverse transcription-coupled PCR technique, it was shown that RAR gamma Bm382 is expressed at different levels in various mouse tissues and that the level of its expression does not correlate with that of normal RAR gamma B. Cotransfection studies revealed that RAR gamma Bm382 acts as a repressor of normal RARs in a promoter- and cell-type-specific manner. Transcription of beta RARE and TREinv promoters was inhibited by RAR gamma Bm382 in both HeLa and F9 cells. Unlike these two promoters, however, RAR gamma Bm382 did not inhibit transcription of the TREpal promoter in HeLa cells but did so in F9 cells. Moreover, while transcription of the lamRARE promoter was inhibited by RAR gamma Bm382 in both HeLa and F9 cells, the inhibition was not observed when F9 cells were induced to differentiate with retinoic acid and dibutyryl cyclic AMP. DNA-binding analysis revealed that RAR gamma Bm382 is able to form a heterodimer with the retinoid X receptor and bind to the different types of retinoic acid response elements with almost the same efficiency as normal RAR. By comparison with effects of other truncation mutants created in vitro, it was suggested that the C-terminal end of the ligand binding domain of RAR is crucial for determining the specificity of transactivation by RAR. Given these observations, we discuss the possibility that protein factors which mediate retinoic acid response element- and cell-type-specific transactivation by RAR are present.

scholarly journals E3, a hematopoietic-specific transcript directly regulated by the retinoic acid receptor alpha

Blood ◽  
1996 ◽  
Vol 88 (7) ◽  
pp. 2517-2530 ◽  
Author(s):  
LM Scott ◽  
L Mueller ◽  
SJ Collins
Keyword(s):  
Retinoic Acid ◽  
Retinoic Acid Receptor ◽  
Immediate Early ◽  
Specific Gene ◽  
Mrna Levels ◽  
Retinoic Acid Receptor Alpha ◽  
Granulocytic Differentiation ◽  
Acid Receptor ◽  
Receptor Alpha ◽  
Alpha Gene

Retinoic acid (RA)-induced maturation mediated by the retinoic acid receptor alpha (RAR alpha) has been implicated in myeloid development. We have used differential hybridization analysis of a cDNA library constructed from the murine RA-inducible MPRO promyelocyte cell line to identify immediate-early genes induced by RA during granulocytic differentiation. E3, one of nine sequences identified, was upregulated in an immediate-early manner, with transcript levels peaking after 60 minutes exposure to RA. E3 transcripts were RA-inducible in HL60 cells, but not in an RA-resistant subclone, HL60R, that harbors a mutated RAR alpha gene. However, when HL60R cells were transduced with a functional copy of the RAR alpha gene, RA induced a 10-fold increase in E3 mRNA levels. E3 transcripts are present in the myeloid, B-lymphoid, and erythroid lineages, absent in nonhematopoietic cells, and encode a highly hydrophobic, potentially phosphorylated polypeptide of unknown function with significant homology to a putative protein expressed in myeloid cells. The murine E3 promoter harbors a single bipartite retinoic acid response element which in transient transfection assays conferred RA sensitivity. These results indicate that E3 is a hematopoietic-specific gene that is an immediate target for the activated RAR alpha during myelopoiesis.

Comparison of gene regulatory networks to identify pathogenic genes for lymphoma

2020 ◽  
Vol 18 (05) ◽  
pp. 2050029
Author(s):  
Xiao Yu ◽  
Tongfeng Weng ◽  
Changgui Gu ◽  
Huijie Yang
Keyword(s):  
Retinoic Acid ◽  
Environmental Factors ◽  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Retinoic Acid Receptor ◽  
Specific Gene ◽  
Acid Receptor ◽  
Cancer Pathways ◽  
Pathogenic Genes ◽  
Gene Regulatory

Lymphoma is the most complicated cancer that can be divided into several tens of subtypes. It may occur in any part of body that has lymphocytes, and is closely correlated with diverse environmental factors such as the ionizing radiation, chemocarcinogenesis, and virus infection. All the environmental factors affect the lymphoma through genes. Identifying pathogenic genes for lymphoma is consequently an essential task to understand its complexity in a unified framework. In this paper, we propose a new method to expose high-confident edges in gene regulatory networks (GRNs) for a total of 32 organs, called Filtered GRNs (f-GRNs), comparison of which gives us a proper reference for the Lymphoma, i.e. the B-lymphocytes cells, whose f-GRN is closest with that for the Lymphoma. By using the Gene Ontology and Biological Process analysis we display the differences of the two networks’ hubs in biological functions. Matching with the Genecards shows that most of the hubs take part in the genetic information transmission and expression, except a specific gene of Retinoic Acid Receptor Alpha (RARA) that encodes the retinoic acid receptor. In the lymphoma, the genes in the RARA ego-network are involved in two cancer pathways, and the RARA is present only in these cancer pathways. For the lymphoid B cells, however, the genes in the RARA ego-network do not participate in cancer-related pathways.

scholarly journals Is PPARβ/δa Retinoid Receptor?

PPAR Research ◽  
2007 ◽  
Vol 2007 ◽  
pp. 1-5 ◽  
Author(s):  
Daniel C. Berry ◽  
Noa Noy
Keyword(s):  
Retinoic Acid ◽  
Fatty Acid Binding Protein ◽  
Nuclear Translocation ◽  
Retinoic Acid Receptor ◽  
Binding Protein ◽  
Retinoid Receptor ◽  
Expression Ratio ◽  
Fatty Acid Binding ◽  
Bona Fide ◽  
Crabp Ii

The broad ligand-binding characteristic of PPARβ/δhas long hampered identification of physiologically-meaningful ligands for the receptor. The observations that the activity of PPARβ/δis supported by fatty acid binding protein 5 (FABP5), which directly delivers ligands from the cytosol to the receptor, suggest thatbona fidePPARβ/δligands both activate the receptor, and trigger the nuclear translocation of FABP5. Using these criteria, it was recently demonstrated that all-trans-retinoic acid (RA), the activator of the classical retinoic acid receptor RAR, also serves as a ligand for PPARβ/δ. Partitioning of RA between its two receptors was found to be regulated by FABP5, which delivers it to PPARβ/δ, and cellular RA binding protein II (CRABP-II), which targets it to RAR. Consequently, RA activates PPARβ/δin cells that display a high FABP5/CRABP-II expression ratio. It remains to be clarified whether compounds other than RA may also serve as endogenous activators for this highly promiscuous protein.

Mutation of Cellular Retinoic Acid-Binding Protein-II (Crabp-II) Does Not Account for Resistance to All-Trans Retinoic Acid (ATRA) in Relapse Acute Promyelocytic Leukemia (APL).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2081-2081
Author(s):  
Binu-John Sankoorikal ◽  
Da-Cheng Zhou ◽  
Peter H. Wiernik ◽  
Robert E. Gallagher
Keyword(s):  
Retinoic Acid ◽  
Target Genes ◽  
Retinoic Acid Receptor ◽  
Treated Patient ◽  
Coding Region ◽  
Treatment Regimens ◽  
All Trans Retinoic Acid ◽  
Negative Role ◽  
Multiple Relapse ◽  
Crabp Ii

Abstract An increase in CRABP-II has frequently been invoked as a cause of resistance to ATRA in APL due to cytoplasmic sequestration and catabolism of ATRA. However, recent evidence indicates that CRABP-II has a positive rather than a negative role in ATRA activity by facilitating delivery of ATRA to retinoic acid receptor-alpha (RARα) associated with ATRA target genes in the cell nucleus or/and by serving as a co-activator of RARα-regulated transcription. This implies that if CRABP-II has a role in the development of ATRA resistance in APL, this would more likely occur through a deficiency rather than from an increase in CRABP-II. We previously reported that CRABP-II is constitutively expressed at similar levels in pretreatment and relapse APL cells (Zhou, et al, Cancer Res58, 5770, 1998), suggesting that putative CRABP-II deficiency is not due to the loss of CRABP-II expression. To investigate the alternative possibility that CRABP-II deficiency might arise through inactivating mutations, we sequenced the entire coding region of CRABP-II from 18 cases of APL who had relapsed from prior ATRA-containing treatment regimens. In 8 cases RNA was transcribed by reverse transcriptase to cDNA and amplified by polymerase chain reaction (PCR), using primers anchored in the 5′ and 3′ untranslated region of mRNA; in 10 cases, genomic DNA was PCR amplified for sequence analysis, using primers anchored in the introns between the 4 exons of the gene. No CRABP-II mutations were identified. The samples tested included 11 first-relapse cases, 2 of whom were refractory to reinduction therapy with intravenous liposomal-ATRA, and 7 multiple relapse cases, all of whom were clinically refractory to ATRA and had, additionally, relapsed from arsenic trioxide therapy. Also, no mutations were found in 3 APL patients who had relapsed from chemotherapy-induced remissions or in 3 APL cell lines (NB4, UF-1 and AP-1060). Two heterozygous base substitutions were incidentally identified in CRABP-II intron 2 in a chemotherapy-only treated patient. These results indicate that CRABP-II mutations rarely, if ever, contribute to ATRA-resistance or disease relapse in APL.

scholarly journals Retinoid receptors cause distortion of the retinoic acid response element in the phosphoenolpyruvate carboxykinase gene promoter

1995 ◽  
Vol 310 (2) ◽  
pp. 483-490 ◽  
Author(s):  
D K Scott ◽  
R K Hall ◽  
D K Granner
Keyword(s):  
Retinoic Acid ◽  
Conformational Changes ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Retinoic Acid Receptor ◽  
Gene Promoter ◽  
Ring Closure ◽  
Retinoid Receptors ◽  
Retinoic Acid Response Element ◽  
Cyclization Kinetics ◽  
Distortion Angle

Functional retinoic acid response elements (RAREs) have been described wherein the direct repeats are separated by 1, 2 or 5 bp (termed DR1, DR2 and DR5 respectively). We have previously shown that retinoic acid receptor/retinoid X receptor (RAR/RXR) binds a DR1 RARE within the phosphoenolpyruvate carboxykinase (PEPCK) gene promoter and is the trans-acting complex that mediates the retinoic acid (RA) response. However, the mechanism of trans-activation is unknown. The consequences of RAR/RXR binding to the PEPCK RARE were examined using a circular permutation analysis as a first step to explore the possible role of DNA conformational changes in the RA response. The RAR/RXR heterodimer produced a distortion angle of 78 degrees. The DNA distortion was shown to be at the centre of the PEPCK RARE; RA did not affect the severity of the distortion angle or the location of the distortion centre. Monomers and homodimers of RAR also distorted the DNA, but to a lesser extent than did RAR/RXR. The results of a phasing analysis demonstrated that RAR/RXR heterodimers did not induce a static DNA bend, in either the presence or the absence of RA. A cyclization kinetics assay was employed to show that RAR/RXR binding affected DNA ring closure in a phase-sensitive, RA-insensitive, manner. Taken together, these observations support the idea that RAR/RXR heterodimers distort the structure of the PEPCK RARE, at least in part, by altering DNA flexibility. The conformational change in the PEPCK RARE upon RAR/RXR binding has implications for how RAR/RXR heterodimers recognize various RARE structures.

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