MODULATION OF RETINOIC ACID RECEPTOR-ALPHA, GROWTH-FACTORS AND PROTOONCOGENES IN RETINOIC ACID-INDUCED APOPTOSIS OF KI-1 LYMPHOMA CELL-LINE

1994 ◽  
Author(s):  
IJ SU ◽  
ZD LAY ◽  
AL CHENG ◽  
YC CHANG
Keyword(s):  
Retinoic Acid ◽  
Growth Factors ◽  
Cell Line ◽  
Retinoic Acid Receptor ◽  
Lymphoma Cell ◽  
Lymphoma Cell Line ◽  
Retinoic Acid Receptor Alpha ◽  
Acid Receptor ◽  
Receptor Alpha ◽  
Induced Apoptosis

scholarly journals A58 REGULATION OF INTESTINAL EPITHELIAL THYMIC STROMAL LYMPHOPOIETIN GENE EXPRESSION BY RETINOIC ACID RECEPTOR ALPHA

2020 ◽  
Vol 3 (Supplement_1) ◽  
pp. 68-69
Author(s):  
R Mahmood ◽  
R Chan ◽  
P Beck ◽  
H Jijon
Keyword(s):  
Retinoic Acid ◽  
Cell Line ◽  
Retinoic Acid Receptor ◽  
Thymic Stromal Lymphopoietin ◽  
Immune Homeostasis ◽  
Intestinal Epithelial ◽  
Retinoic Acid Receptor Alpha ◽  
Acid Receptor ◽  
Receptor Alpha ◽  
Selective Agonist

Abstract Background We have targeted the retinoic acid receptor alpha (RARα) isoform in murine intestinal epithelial cells (IECs) to explore the role of epithelial intrinsic retinoid signaling in intestinal immune homeostasis. We noted a significant decrease in the CD11c+ and CD103+ dendritic cell (DC) subpopulations in the intestines of intestinal-epithelial specific RARα-deficient (RARα villin) mice. In the present study, we identified Thymic Stromal Lymphopoietin (TSLP) as a contributing factor that influences intrinsic RARα signaling within IECs. This cytokine preferentially stimulates CD103+ DCs to a more tolerogenic phenotype in the GI tract, induces Tregs and drives TH2 polarization. TSLP also influences immune homeostasis by modulating the activation of myeloid cells, inhibition of proinflamamtory DCs, and production of IL-12. Notably, TSLP levels are decreased in Crohn’s disease (CD) where inflammation is driven by IL-12. Aims We hypothesize that RA intrinsic signaling within IECs modulates TSLP expression via activation of RARα. We sought to generate a RARα -/- murine intestinal epithelial cell line utilizing the CRISPR/CAS9 system to examine the effects of RARa ablation. Second, we aim to establish RARα’s role in regulating intestinal epithelial TSLP expression in both the RARα villin mice and the CRISPR-generated RARα -/- cell line. Methods Exon 5 in the open reading frame of the RARα gene in Mode-K murine IECs was targeted using CRISPR/CAS9. CRISPR cleavage and knockdown of RARα activity was confirmed via surveyor/luciferase assays. The cell lines were phenotyped with regards to their morphology, proliferative ability, and viability. Next, we examined TSLP mRNA expression in the colons of RARα villin mice and the CRISPR RARα -/- knockout cell line via qRT-PCR under baseline and stimulated conditions. Wild-type (WT) and RARα-/- cells were stimulated with RARα-selective agonist, BMS753, and muramyl dipeptide (MDP), a NOD2-selective agonist. Results TSLP expression in surface colonic epithelium was elevated 2.3-fold in RARα villin mice compared to WT litter mates. TSLP expression was elevated 10-fold in the Mode-K RARα-/- cells versus parent cells at baseline. BMS753 stimulation resulted in a 15-fold increase in TSLP expression in the RARα-/- cells compared to baseline. When stimulated with MDP, a NOD2-selective agonist known to stimulate TSLP expression, TSLP expression was elevated 60-fold in the RARα-/- cells, but significantly impaired compared to the WT cells (400-fold). Conclusions TSLP expression is controlled by RARα in colonic IECs where it may act as a repressor of TSLP promoter transactivation under baseline conditions. This suggests an important role for RA on myeloid and T cell function via effects on intestinal epithelial TSLP expression. Funding Agencies CCCUniversity of Calgary, Department of Medicine

Retinoic Acid Receptor Alpha Amplifications and Retinoic Acid Sensitivity in Breast Cancers

2013 ◽  
Vol 13 (5) ◽  
pp. 401-408 ◽  
Author(s):  
Samar Alsafadi ◽  
Caroline Even ◽  
Coralie Falet ◽  
Aicha Goubar ◽  
Frédéric Commo ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Retinoic Acid Receptor ◽  
Breast Cancers ◽  
Retinoic Acid Receptor Alpha ◽  
Acid Sensitivity ◽  
Acid Receptor ◽  
Receptor Alpha

Retinoic Acid Receptor Alpha (RARα) Fusion Genes in Leukemia

2017 ◽  
pp. 271-285
Author(s):  
Ganesan Padmavathi ◽  
Javadi Monisha ◽  
Anand Anip ◽  
Krishan Kumar Thakur ◽  
Ajaikumar B. Kunnumakkara
Keyword(s):  
Retinoic Acid ◽  
Retinoic Acid Receptor ◽  
Fusion Genes ◽  
Retinoic Acid Receptor Alpha ◽  
Acid Receptor ◽  
Receptor Alpha

Inhibitory Effects of Retinoic Acid Receptor Alpha Stimulants on Murine Cataractogenesis through Suppression of Deregulated Calpains

2007 ◽  
Vol 48 (5) ◽  
pp. 2224 ◽  
Author(s):  
Nami Nishikiori ◽  
Makoto Osanai ◽  
Hideki Chiba ◽  
Takashi Kojima ◽  
Hiroshi Ohguro ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Retinoic Acid Receptor ◽  
Inhibitory Effects ◽  
Retinoic Acid Receptor Alpha ◽  
Acid Receptor ◽  
Receptor Alpha

scholarly journals Characterization of a functional promoter for the human retinoic acid receptor-alpha (hRAR-α)

1990 ◽  
Vol 18 (23) ◽  
pp. 6799-6806 ◽  
Author(s):  
Nigel J. Brand ◽  
Martin Petkovich ◽  
Pierre Chambon
Keyword(s):  
Retinoic Acid ◽  
Retinoic Acid Receptor ◽  
Retinoic Acid Receptor Alpha ◽  
Acid Receptor ◽  
Receptor Alpha

Expression of retinoic acid receptor alpha mRNA in human leukemia cells

Blood ◽  
1989 ◽  
Vol 74 (1) ◽  
pp. 99-102 ◽  
Author(s):  
C Largman ◽  
K Detmer ◽  
JC Corral ◽  
FM Hack ◽  
HJ Lawrence
Keyword(s):  
Retinoic Acid ◽  
Cell Lines ◽  
Retinoic Acid Receptor ◽  
Leukemia Cell ◽  
Leukemia Cells ◽  
Human Leukemia ◽  
Retinoic Acid Receptor Alpha ◽  
Acid Receptor ◽  
Receptor Alpha ◽  
Human Leukemia Cells

The expression of the newly described human retinoic acid receptor alpha (RAR alpha) in six nonlymphoid and six lymphoid leukemia cell lines and nine freshly obtained samples of leukemia cells from patients with acute nonlymphoid leukemia was assessed by Northern blot analysis, using a full length cDNA clone of RAR alpha as probe. RAR alpha was expressed in all 12 cell lines and in all fresh leukemia samples as two major transcripts of 2.6 and 3.5 kb in size. Levels of RAR alpha expression and transcript sizes in retinoid-sensitive cells (such as HL60 or fresh promyelocytic leukemia cells) were not different from those in other samples. Moreover, expression of RAR alpha was not significantly modulated by exposure to cis-retinoic acid (cisRA) in either cisRA-responsive or unresponsive cells. By using a 3′ fragment of the RAR alpha gene as a probe, we confirmed that the transcripts visualized did not represent the homologous RAR beta gene. RAR alpha appears to be expressed in most human leukemia cells regardless of the type of biologic response to retinoic acid.

A biomarker-directed phase 2 trial of SY-1425, a selective retinoic acid receptor alpha agonist, in adult patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS7071-TPS7071
Author(s):  
Rachel J. Cook ◽  
Eytan Stein ◽  
David P. Steensma ◽  
Mikkael A. Sekeres ◽  
Dale L. Bixby ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Lower Risk ◽  
Retinoic Acid Receptor ◽  
Survival Duration ◽  
Myeloid Differentiation ◽  
Clinical Effects ◽  
Retinoic Acid Receptor Alpha ◽  
Differentiation Markers ◽  
Acid Receptor ◽  
Receptor Alpha

TPS7071 Background: SY-1425 (tamibarotene) is an orally available, synthetic retinoid approved in Japan for the treatment of relapsed/refractory (R/R) APL. SY-1425 is a more potent and selective retinoic acid receptor alpha (RARα) agonist with improved pharmacologic properties compared to all-trans retinoic acid (ATRA) including increased half-life and lack of metabolism by CYP26A1 resulting in extended relative exposures. SY-1425 binding to RARα relieves pathogenic repression of myeloid differentiation. Super-enhancers associated with RARA and upregulation of RARA expression correlate with increased sensitivity to SY-1425 in vitro and predict for response to SY-1425 with induced differentiation and reduced proliferation in RARA-high PDX AML models, but not in RARA-low models. SY-1425 also induces the RARα target gene DHRS3 in RARA-high AML cell lines. This study is designed to demonstrate pharmacodynamic (PD) and clinical effects of SY-1425 in non-APL AML and MDS patients (pts) positive for the RARA super-enhancer associated biomarker or exploratory RARA pathway biomarker, IRF8. Methods: This study is enrolling pts with R/R AML, R/R higher-risk MDS, newly-diagnosed AML ≥60 yrs unlikely to respond to or tolerate standard therapy, and transfusion dependent lower-risk MDS pts without del 5q who are unlikely to respond to or have failed ESAs. Pts must be biomarker positive based on centralized testing of tumor cells from blood. All pts receive SY-1425 at 6 mg/m2/day PO with continuous twice daily dosing. Primary objectives are to characterize the activity of SY-1425 by ORR in AML and higher-risk MDS pts or transfusion independence in lower-risk MDS pts. Secondary objectives include event-free and relapse-free survival, duration of response, overall survival, hematologic improvement and safety. PD evaluation includes induction of DHRS3 and expression of myeloid differentiation markers. Target enrollment is 80 pts. This trial opened in September 2016. Through a protocol amendment, SY-1425 treatment in combination with azacitidine will also be evaluated. ClinicalTrials.gov identifier: NCT02807558.

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