Regulation of vitamin D receptor expression by retinoic acid receptor alpha in acute myeloid leukemia cells

Marchwicka, Aleksandra; Cebrat, Malgorzata; Laszkiewicz, Agnieszka; Sniezewski, Lukasz; Brown, Geoffrey; Marcinkowska, Ewa

doi:10.1016/j.jsbmb.2016.03.013

Cited by 26 publications

(36 citation statements)

References 33 publications

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“…Together, these results indicate a putative RA/c-Raf/GSK-3/RARα axis that is susceptible to RRD-251 and represents a novel regulatory pathway for RA differentiation that may extend its utility beyond APL to other myeloid leukemias. Additionally RRD-251 may have further potential in combination therapies for leukemic differentiation utilizing 1,25-dihydroxy vitamin D3 as GSK-3 and RARα were recently found to regulate VDR expression and transcriptional activity [41-43]. …”

Section: Discussionmentioning

confidence: 99%

RRD-251 enhances all-trans retinoic acid (RA)-induced differentiation of HL-60 myeloblastic leukemia cells

et al. 2016

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All-trans-retinoic acid (RA) is known to induce terminal granulocytic differentiation and cell cycle arrest of HL-60 cells. Responding to an RA-induced cytosolic signaling machine, c-Raf translocates to the nucleus, providing propulsion for RA-induced differentiation. This novel mechanism is not understood, but presumably reflects c-Raf binding with nuclear gene regulatory proteins. RRD-251 is a small molecule that prevents the interaction of c-Raf and RB, the retinoblastoma tumor suppressor protein. The involvement of c-Raf and RB in RA-induced differentiation motivates interest in the effects of combined RA and RRD-251 treatment on leukemic cell differentiation.We demonstrate that RRD-251 enhances RA-induced differentiation. Mechanistically, we find that nuclear translocated c-Raf associates with pS608 RB. RA causes loss of pS608 RB, where cells with hypophosphorylated S608 RB are G0/G1 restricted. Corroborating the pS608 RB hypophosphorylation, RB sequestration of E2F increased with concomitant loss of cdc6 expression, which is known to be driven by E2F. Hypophosphorylation of S608 RB releases c-Raf from RB sequestration to bind other nuclear targets. Release of c-Raf from RB sequestration results in enhanced association with GSK-3 which is phosphorylated at its S21/9 inhibitory sites. c-Raf binding to GSK-3 is associated with dissociation of GSK-3 and RARα, thereby relieving RARα of GSK-3 inhibition. RRD-251 amplifies each of these RA-induced events. Consistent with the posited enhancement of RARα transcriptional activity by RRD-251, RRD-251 increases the RARE-driven CD38 expression per cell. The RA/c-Raf/GSK-3/RARα axis emerges as a novel differentiation regulatory mechanism susceptible to RRD-251, suggesting enhancing RA-effects with RRD-251 in therapy.

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Section: Discussionmentioning

confidence: 99%

RRD-251 enhances all-trans retinoic acid (RA)-induced differentiation of HL-60 myeloblastic leukemia cells

et al. 2016

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“…It is known that RXRs heterodimerise with both RARs and NR4A receptors, but RARs and NR4A receptors do not heterodimerise to one another. Currently, there is no literature relating the RARs directly with the NR4As, in particular NR4A2, although a recent study has found that RARs regulate VDR transcription [71]. This hemispheric asymmetry supports findings of the left hemisphere being more pathologically impaired in schizophrenia compared to the right [68-70].…”

Section: Discussionmentioning

confidence: 67%

Nuclear Receptors and Neuroinflammation in Schizophrenia

et al. 2017

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Introduction: Several nuclear receptor family members have been associated with schizophrenia and inflammation. Vitamins A and D exert anti-inflammatory actions, but their receptors (mainly nuclear receptors) have not been extensively studied in either schizophrenia brains or in association with neuroinflammation. We examined the expression of vitamin A (RARs and RXRs) and vitamin D and protein disulphide-isomerase A3 (PDIA3) receptors, as well as nuclear orphan receptors (NR4As), in the context of elevated cytokine expression in the dorsolateral prefrontal cortex (DLPFC). Methods: mRNA levels of nuclear receptors were measured in DLPFC tissues via RT-qPCR. ANCOVAs comparing high inflammation schizophrenia, low inflammation schizophrenia and low inflammation control groups were performed. Results: RARG, RXRB, NR4A1 and NR4A3 transcripts showed significant differential expression across the three groups (ANCOVA p = 0.02–0.001). Post hoc testing revealed significant reductions in RARG expression in schizophrenia with low inflammation compared to schizophrenia with high inflammation and to controls, and RXRB mRNA was significantly reduced in schizophrenia with low inflammation compared to controls. NR4A1 and NR4A3 mRNAs were decreased in schizophrenia with high inflammation compared to schizophrenia with low inflammation, with NR4A1 also significantly different to controls. Conclusion: In schizophrenia, changes in nuclear receptor mRNA levels involved with mediating actions of vitamin A derivatives vary according to the inflammatory state of brains.

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“…Past research indicated a synergistic cancer differentiation effect by using a combination of 1,25D and ATRA [11]. However, our recent experiments have revealed that in AML cell lines the effect of combination treatment varies, due to either down- or upregulation of VDR expression in response to ATRA, depending on the AML cell line examined [12,13]. …”

Section: Introductionmentioning

confidence: 99%

“…Our recent experiments have revealed a new exon, 1g, regulated from the promoter of exon 1a. Exon 1g is used in VDR transcripts present in AML cells [13]. Multiple publications confirm that VDR expression in humans is regulated in response to ATRA [12,21,22,23], while there are conflicting reports concerning regulation of human VDR by 1,25D [13,24,25,26].…”

Section: Introductionmentioning

confidence: 99%

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Diverse Regulation of Vitamin D Receptor Gene Expression by 1,25-Dihydroxyvitamin D and ATRA in Murine and Human Blood Cells at Early Stages of Their Differentiation

Janik

Nowak

Laszkiewicz

et al. 2017

IJMS

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Vitamin D receptor (VDR) is present in multiple blood cells, and the hormonal form of vitamin D, 1,25-dihydroxyvitamin D (1,25D) is essential for the proper functioning of the immune system. The role of retinoic acid receptor α (RARα) in hematopoiesis is very important, as the fusion of RARα gene with PML gene initiates acute promyelocytic leukemia where differentiation of the myeloid lineage is blocked, followed by an uncontrolled proliferation of leukemic blasts. RARα takes part in regulation of VDR transcription, and unliganded RARα acts as a transcriptional repressor to VDR gene in acute myeloid leukemia (AML) cells. This is why we decided to examine the effects of the combination of 1,25D and all-trans-retinoic acid (ATRA) on VDR gene expression in normal human and murine blood cells at various steps of their development. We tested the expression of VDR and regulation of this gene in response to 1,25D or ATRA, as well as transcriptional activities of nuclear receptors VDR and RARs in human and murine blood cells. We discovered that regulation of VDR expression in humans is different from in mice. In human blood cells at early stages of their differentiation ATRA, but not 1,25D, upregulates the expression of VDR. In contrast, in murine blood cells 1,25D, but not ATRA, upregulates the expression of VDR. VDR and RAR receptors are present and transcriptionally active in blood cells of both species, especially at early steps of blood development.

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Regulation of vitamin D receptor expression by retinoic acid receptor alpha in acute myeloid leukemia cells

Cited by 26 publications

References 33 publications

RRD-251 enhances all-trans retinoic acid (RA)-induced differentiation of HL-60 myeloblastic leukemia cells

RRD-251 enhances all-trans retinoic acid (RA)-induced differentiation of HL-60 myeloblastic leukemia cells

Nuclear Receptors and Neuroinflammation in Schizophrenia

Diverse Regulation of Vitamin D Receptor Gene Expression by 1,25-Dihydroxyvitamin D and ATRA in Murine and Human Blood Cells at Early Stages of Their Differentiation

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