Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P15088 (mast cell)
 14,925 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The retinoic acid receptor (RAR alpha) is expressed in virtually all hematopoietic lineages, but the role of this transcription factor in regulating the growth and differentiation of hematopoietic progenitors is unknown. We have constructed a mutant RAR alpha that both exhibits dominant-negative activity against the normal RAR alpha in transient expression assays in mouse fibroblasts and inhibits retinoic acid-induced neutrophilic differentiation of the HL-60 human promyelocytic leukemia cell line. When this dominant-negative RAR alpha construct is introduced into the multipotent interleukin-3-dependent FDCP mix A4 murine hematopoietic cell line, there is a rapid switch from spontaneous neutrophil/monocyte differentiation to basophil/mast cell development. Thus, in this multipotent hemopoietic cell line the normal RAR alpha transcription factor and/or related molecules appear to promote the differentiation of neutrophils and monocytes but suppress the development of basophils/mast cells.
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PMID:A mutated retinoic acid receptor-alpha exhibiting dominant-negative activity alters the lineage development of a multipotent hematopoietic cell line. 133 22

We examined the effects of retinoids on the human mast cell development using a serum-deprived culture system. When 10-week cultured mast cells derived from CD34(+) cord blood cells were used as target cells, both all-trans retinoic acid (ATRA) and 9-cis RA inhibited the progeny generation under stimulation with stem cell factor (SCF) in a dose-dependent manner (the number of progeny grown by SCF plus RA at 10(-7) mol/L was one tenth of the value obtained by SCF alone). The early steps in mast cell development appear to be less sensitive to RA according to the single CD34(+)c-kit(+) cord blood cell culture study. The optimal concentration of RAs also reduced the histamine concentration in the cultured mast cells (3.00 +/- 0.47 pg per cell in SCF alone, 1.44 +/- 0.18 pg per cell in SCF+ATRA, and 1.41 +/- 0.10 pg per cell in SCF+9-cis RA). RT-PCR analyses showed the expression of RARalpha, RARbeta, RXRalpha, and RXRbeta messenger ribonucleic acid (mRNA) in 10-week cultured mast cells. The addition of an RAR-selective agonist at 10(-10) mol/L to 10(-7) mol/L decreased the number of mast cells grown in SCF, whereas an RXR-selective agonist at up to 10(-8) mol/L was inactive. Among RAR subtype selective retinoids used at 10(-9) mol/L to 10(-7) mol/L, only the RARalpha agonist was equivalent to ATRA at 10(-7) mol/L in its ability to inhibit mast cell growth. Conversely, the addition of excess concentrations of a RARalpha antagonist profoundly counteracted the retinoid-mediated suppressive effects. These results suggest that RA inhibits SCF-dependent differentiation of human mast cell progenitors through a specific receptor. (Blood. 2000;95:2821-2828)
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PMID:Retinoic acid is a negative regulator for the differentiation of cord blood-derived human mast cell progenitors. 1077 27

Investigation of mast cell responsiveness toward retinoic acid (RA) revealed selective promotion of ICAM-3 expression in the human mast cell line HMC-1. This process was dose- and time-dependent and detectable by flow cytometry, Western blot analysis, ELISA, and Northern blot analysis. ICAM-3 modulation was found to be cell-type dependent, detectable also for HL-60 cells and monocytes but not U-937 and only weakly for KU812 cells. Terminally differentiated skin mast cells also failed to up-modulate their ICAM-3, suggesting the requirement for some degree of immaturity for the process. RA-mediated effects on ICAM-1 expression, studied in parallel, were clearly distinct from those on ICAM-3. Investigation of retinoid receptor expression, known to mediate intracellular RA signaling, revealed presence of RAR alpha, RAR gamma, RXR beta, and RXR gamma transcripts in all cell lines studied, and HMC-1 cells were the only line lacking RXR alpha. RAR beta, not expressed at baseline, was induced by RA in a fashion obviously correlating with ICAM-3 up-regulation. Increased ICAM-3 expression was of functional significance, such that processes stimulated or co-stimulated via ICAM-3 (homotypic aggregation, IL-8 secretion) were clearly enhanced upon RA pretreatment, suggesting that RA may contribute via hitherto unrecognized pathways to immune function and host defense.
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PMID:Retinoic acid up-regulates myeloid ICAM-3 expression and function in a cell-specific fashion--evidence for retinoid signaling pathways in the mast cell lineage. 1126 82

Stem cell factor plays a key role in the development of human mast cells via interaction with Kit receptor. We and other groups have previously shown that a number of cytokines can regulate the stem-cell-factor-dependent development of mast cells in vitro. In this study we investigated the effect of retinoic acid on human mast cells in vitro and in vivo. Retinoids are known to have strong modulatory effects on hematopoietic differentiation. We found that all-trans-retinoic acid, at concentrations as low as 1 nM, inhibits the stem-cell-factor-dependent differentiation of mast cells in vitro. This effect of retinoic acid was found to be on progenitor cells, whereas more mature mast cells were less affected. The use of specific agonists binding either to the RAR or the RXR nuclear receptors indicated involvement of both the RAR/RXR and RXR/RXR pathways in inhibiting mast cell differentiation. In contrast to the effects on mast cell progenitors, retinoic acid had no effect on the number of mature mast cells in skin organ cultures. Furthermore, topical treatment of normal skin with a retinoic-acid-containing cream caused an increase in the number of tryptase-positive mast cells, whereas the numbers of the major cutaneous mast cell type, tryptase- and chymase-positive mast cells, remained unaffected. Our results suggest that retinoic acid suppresses commitment of progenitor cells into the mast cell lineage and/or acts on early mast cell progenitors, whereas mature cutaneous mast cells are less susceptible to retinoic acid.
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PMID:Retinoic acid inhibits in vitro development of mast cells but has no marked effect on mature human skin tryptase- and chymase-positive mast cells. 1254 29