Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Retinoic acid (RA) has been shown to regulate cellular growth and differentiation of a variety of cell types, including cells of the myelomonocytic lineage. We used the monocytic leukaemia cell line THP-1, which differentiates to macrophages in response to phorbol 12-myristate 13-acetate (PMA), to investigate the regulation by RA of genes in the scavenger receptor type B family (CD36) in human monocyte/macrophages. Reverse transcription-polymerase chain reaction and flow cytometry demonstrated that, like PMA and the natural peroxisome-proliferator-activated receptor-gamma (PPARgamma) ligand 15d-PGJ2, RA induced CD36 gene expression in these cells. Moreover, RA plus 15d-PGJ2 further enhanced CD36 protein and mRNA levels over that seen with the RA or PPARgamma compounds alone. The PPARgamma antagonist GW9662 was shown to block completely PPARgamma-ligand induction of CD36 gene expression, but had little effect on the action of RA. Our data indicated that RXR- and RAR-specific ligands (LG153 and TTNPB, respectively) were each alone able to increase CD36 mRNA and surface protein levels. By using calphostin C, a specific protein kinase C (PKC) inhibitor, we demonstrated that induction of CD36 by PMA, as well as by PPARgamma and RXR ligands were dependent upon PKC activation. In contrast, activation of CD36 through the RAR pathway was not affected by inhibition of PKC activity. Taken together, these data demonstrate that RA can up-regulate CD36 expression in human monocytes/macrophages. This regulation appears to be predominantly mediated through the RAR/RXR pathway of action and, unlike previously described methods of CD36 modulation, is independent of PPARgamma and PKC signalling. This study suggests a possible role for RA in physiological processes involving the scavenger receptor function in cells of the monocyte/macrophage lineage.
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PMID:Peroxisome-proliferator-activated-receptor gamma (PPARgamma) independent induction of CD36 in THP-1 monocytes by retinoic acid. 1197 32

The product of the blr1 gene is a CXC chemokine receptor (CXCR5) that regulates B lymphocyte migration and has been implicated in myelomonocytic differentiation. The U937 human leukemia cell line was used to study the role of blr1 in retinoic acid-regulated monocytic leukemia cell growth and differentiation. blr1 mRNA expression was induced within 12 hr by retinoic acid in U937 cells. To determine whether the early induction of blr1 might regulate inducible monocytic cell differentiation, U937 cells were stably transfected with blr1 (U937/blr1 cells). Ectopic expression of blr1 caused no significant cell cycle or differentiation changes, but caused the U937/blr1 cells to differentiate faster when treated with either retinoic acid or 1alpha,25-dihydroxyvitamin D(3). Treated with retinoic acid, U937/blr1 cells showed a greater increase in the percentage of CD11b expressing cells than vector control cells. Retinoic acid also induced a higher percentage of functionally differentiated blr1 transfectants as assessed by nitroblue tetrazolium reduction. U937/blr1 cells underwent moderate growth inhibition on treatment with retinoic acid. Similar results occurred with 1alpha,25-dihydroxyvitamin D(3). Because blr1 was induced early during cell differentiation and because its overexpression accelerated monocytic differentiation, it may be important for signals controlling cell differentiation.
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PMID:Ectopic expression of CXCR5/BLR1 accelerates retinoic acid- and vitamin D(3)-induced monocytic differentiation of U937 cells. 1232 54

Retinoic acid is known to cause the cell cycle arrest and myeloid differentiation of HL-60 myeloblastic leukemia cells. Evidence suggesting the possible involvement of the Fc gammaRII immunoglobulin receptor in mediating retinoic acid-induced growth arrest and differentiation of HL-60 cells is presented. HL-60 cells stably transfected with the delta205 mutant polyoma middle T antigen, a largely debilitated polyoma middle T antigen, are known to undergo accelerated retinoic acid-induced growth arrest and differentiation compared with parental HL-60 cells. Delta205 transfected cells were compared with parental HL-60 cells by differential display to identify differentially expressed genes, which are regulated downstream of delta205 and might facilitate cellular response to retinoic acid. Differential display revealed that the Fc gammaRII immunoglobulin receptor was differentially expressed. HL-60 cells express Fc gammaRIIA but not Fc gammaRIIB. In parental HL-60 cells, retinoic acid up-regulated Fc gammaRII expression, and Fc gammaRII membrane protein expression increased concomitantly with retinoic acid-induced cell cycle arrest and differentiation. Ectopic expression of Fc gammaRIIa1 in HL-60 cells retarded cellular progression through all phases of the cell cycle. For HL-60 cells stably transfected with Fc gammaRIIa1, onset of retinoic acid-induced growth arrest and differentiation occurred in fewer cell cycles than for parental HL-60 cells. Similar results occurred with 1,25-dihydroxy vitamin D3. Retinoic acid-induced tyrosine phosphorylation of various PAGE-detected protein bands in HL-60 cells was enhanced by cross-linking ectopically expressed Fc gammaRIIa1 receptor. The known retinoic acid-induced sustained activation of various mitogen-activated protein kinase signaling molecules, including extracellular signal-regulated kinase 2, src-like kinases, and adapter molecules, may in part reflect induced expression of Fc gammaRIIA, which is known to activate a similar ensemble of signaling molecules through its ITAM domain. The data suggest that retinoic acid induces increased Fc gammaRIIA expression, which is of functional consequence in eliciting growth arrest and differentiation.
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PMID:Retinoic acid-induced growth arrest and differentiation: retinoic acid up-regulates CD32 (Fc gammaRII) expression, the ectopic expression of which retards the cell cycle. 1247 67

Retinoic acid (RA), a potent inducer of cell differentiation, and N-(4-hydroxyphenyl)retinamide (4-HPR, fenretinide), a potent inducer of apoptosis, are well known as anticancer agents that are administered orally to patients for leukemia, breast and prostate cancer, respectively. However, it has not been studied whether both retinoids are effective on metastatic cancer. In mice implanted with M5076 cells, murine reticulum cell sarcoma survival times were prolonged by i.v. treatment of RA and 4-HPR entrapped in liposomes containing soybean-derived sterylglucoside mixture (SG), which accumulates in liver. In contrast, free RA and 4-HPR were inactive. These results indicate that RA and 4-HPR in SG-liposomes exhibit anticancer efficacy on metastatic cancers, and may have great potential for clinical use in the treatment of various cancers.
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PMID:Effects on M5076-hepatic metastasis of retinoic acid and N-(4-hydroxyphenyl) retinamide, fenretinide entrapped in SG-liposomes. 1284 42

Retinoic acid induces clinical remission in acute promyelocytic leukemia (APL) by triggering differentiation of leukemia promyelocytes. Here, we have characterized a gene encoding a member of the immunoglobulin superfamily, among novel retinoic acid-induced genes identified in APL cells. This protein, which was named JAML (junctional adhesion molecule-like), contains 2 extracellular immunoglobulin-like domains, a transmembrane segment, and a cytoplasmic tail. JAML mRNA is expressed in hematopoietic tissues and is prominently expressed in granulocytes. The fact that JAML protein is localized at the cell plasma membrane in the areas of cell-cell contacts, whereas it is not detected at free cell borders, suggests that JAML is engaged in homophilic interactions. Furthermore, a conserved dimerization motif among JAM members was shown to be important for JAML localization at the cell membrane. Finally, exogenous expression of JAML in myeloid leukemia cells resulted in enhanced cell adhesion to endothelial cells. Altogether, our results point to JAML as a novel member of the JAM family expressed on leukocytes with a possible role in leukocyte transmigration.
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PMID:JAML, a novel protein with characteristics of a junctional adhesion molecule, is induced during differentiation of myeloid leukemia cells. 1286 15

Retinoic acid (RA) overcomes the maturation block in t(15:17) acute promyelocytic leukemia (APL), leading to granulocytic differentiation. Patients receiving RA alone invariably develop RA resistance. RA-resistant cells can serve as useful models for the development of treatments for both APL and other leukemias. Previously, we showed that RA and tumor necrosis factor (TNF) promote monocytic differentiation of the APL cell line NB4 and U937 monoblastic cells. Here, we report that combining TNF with RA leads to maturation of several RA-resistant APL cells along a monocytic pathway, whereas UF-1, a patient-derived RA-resistant cell line, showed characteristics of granulocytic differentiation. We found distinct differences in gene regulation between UF-1 cells and cells showing monocytic differentiation. Although IRF-7 was up-regulated by TNF and RA in all cells tested, expression of c-jun and PU.1 correlated with monocytic differentiation. Furthermore, synergistic induction of PU.1 DNA binding and macrophage colony-stimulating factor receptor (m-CSF-1R) mRNA was observed only in cells differentiating into monocytes. Using neutralizing antibodies against m-CSF-1R or its ligand, we found that inhibiting this pathway strongly reduced CD14 expression in response to RA and TNF, suggesting that this pathway is essential for their synergy in RA-resistant leukemia cells.
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PMID:Combination of retinoic acid and tumor necrosis factor overcomes the maturation block in a variety of retinoic acid-resistant acute promyelocytic leukemia cells. 1525 26

Interferon-gamma (IFN-gamma) induces expression of multiple genes in endothelial cells. Retinoic acid-inducible gene-I (RIG-I) encodes a protein belonging to the DExH-box family, but details of its physiological function are not clear. RIG-I is induced in leukemia cells by retinoic acid and in endothelial cells by lipopolysaccharide. In the present study, the authors found that IFN-gamma also induces the expression of RIG-I in human umbilical vein endothelial cells. Induction of RIG-I mRNA by IFN-gamma was not altered by the treatment with cycloheximide or interleukin-4. Fluorescent immunostaining and Western blot analysis revealed cytoplasmic distribution of RIG-I. The in situ endothelium in a normal lung tissue was also found to express RIG-I protein. Although the physiological function of RIG-I is still unknown, induction of RIG-I by IFN-gamma may play an important role in inflammatory or immunological reactions in endothelial cells.
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PMID:Interferon-gamma induces retinoic acid-inducible gene-I in endothelial cells. 1537 Feb 93

Retinoic acid receptor (RAR)beta is perceived to function as a tumor suppressor gene in various contexts where its absence is associated with tumorigenicity and its presence causes cell cycle arrest. Tazarotene is a prodrug selective for RARbeta/gamma, thereby motivating interest in determining whether tazarotene might activate putative tumor suppressor activity. Using HL-60 human myeloblastic leukemia cells, a cell line that undergoes G0 cell cycle arrest and myeloid differentiation in response to retinoic acid (RA), tazarotene failed to cause extracellular signal-regulated kinase (ERK) activation, a requirement for retinoic acid (RA)-induced G0 arrest and differentiation; retinoblastoma (RB) hypophosphorylation, another characteristic of RA-induced G0 arrest and cell differentiation; G0 arrest; or differentiation into mature myeloid cells. However, when used in combination with a retinoid X receptor (RXR)-selective ligand, tazarotene caused ERK activation, RB tumor suppressor protein hypophosphorylation, G0 arrest, and myeloid differentiation. The kinetics of G0 arrest and differentiation was similar to that of RA. Dose-response studies showed that diminishing tazarotene progressively diminished both induced cell differentiation and G0 arrest, where the doses for cellular effects were consistent with the transcriptional transactivation data. For either tazarotene or an RARalpha-selective ligand, diminishing the coadministered RXR-selective ligand diminished both induced differentiation and G0 arrest. Tazarotene could propel either early or late portions of the period leading to differentiation and G0 arrest and was interchangeable with an RARalpha-selective ligand. Tazarotene used with RXR-selective ligand may thus be a useful antineoplastic agent in differentiation induction therapy as exemplified by the prototypical RA treatment of acute promyelocytic leukemia.
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PMID:A retinoic acid receptor beta/gamma-selective prodrug (tazarotene) plus a retinoid X receptor ligand induces extracellular signal-regulated kinase activation, retinoblastoma hypophosphorylation, G0 arrest, and cell differentiation. 1538 24

Retinoic acid (RA), bromodeoxyuridine (BrdU), and the Delta 205 mutant polyoma middle T antigen affect the expression of a common ensemble of proteins in HL-60 human myeloblastic leukemia cells. Each of these agents is known to be able to prime HL-60 cells and accelerate subsequently induced myeloid or monocytic differentiation and G0 cell cycle arrest, suggesting that they have equal or identical cellular targets relevant to the early stages of inducing cell differentiation and G0 arrest. As a test of this possibility, a survey of protein expression changes induced by RA, BrdU, or Delta 205 transfection was performed. Retinoic acid induced numerous changes within h. Bromodeoxyuridine caused larger numbers of changes, whereas Delta 205 caused a more limited number. Among the hundreds of affected proteins detected, there were comparable numbers of up- or downregulated proteins. A small number changed between undetectable and detectable expression. The affected proteins were not restricted to a single functional class and included transcription factors, receptors, signaling molecules, cytoskeletal molecules, and effectors of various cellular processes such as deoxyribonucleic acid replication, transcription, and translation. The intersect of the sets of proteins affected by RA, BrdU, and Delta 205 was identified to determine if these agents regulated a common subset of proteins. This ensemble contained the commonly upregulated proteins AF6, ABP-280, ENC-1, ESE 1, MAP2B, NTF2, casein kinase, IRF1, SRPK2, Rb2, RhoGDI, P47phox, CD45, PKR, and SIIIp15. The commonly downregulated proteins were SHC, katanin, flotillin-2/ESA, EB 1, p43/EMAPIIprecursor, Jab1, FNK. The composition of the ensemble suggested three apparent themes for cellular processes that were affected early. The themes reflected the ultimate fate of the treated precursor cells as a mature myeloid cell, namely a cell whose hallmarks are (1) motility to migrate to a target and phagocytize it, (2) inducible oxidative metabolism to reduce the target with superoxide from a respiratory burst, and (3) biosynthetic slow down consistent with conversion from cell proliferation to quiescence. Interestingly, RA appears to induce aspects of an interferon-like response of potential significance as part of a biosynthetic slow down leading to cell cycle arrest. In conclusion, three biologically disparate ways to prime cells to differentiate were used to filter out a small ensemble of commonly regulated proteins that group as either microtubule associated, oxidative metabolism machinery, or effectors of cellular responses to interferon.
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PMID:retinoic acid, bromodeoxyuridine, and the Delta 205 mutant polyoma virus middle T antigen regulate expression levels of a common ensemble of proteins associated with early stages of inducing HL-60 leukemic cell differentiation. 1563 4

Retinoic acid (RA) can be regarded as a pharmacological agent commonly used for its ability to affect growth and differentiation of a variety of cell types, such as acute promyelocytic leukemic and endothelial cells. In the present work we studied the effect of all-trans-RA (ATRA) and its steroidal analogs EA-4, EA-136 and EA-137 on the growth of human promyelocytic HL-60 cells in vitro. The specific steroidal substrates were chosen in order to further investigate their ability to improve the pharmacological properties of conjugated antileukemic agents. ATRA decreased the number of HL60 cells from the first 24 h after its addition to the cell culture medium. The decrease was significant at concentrations higher than 10(-5) M. All the analogs tested also decreased the number of HL60 cells with an IC50 similar to that of ATRA, except for EA-4 whose IC50 was almost two orders of magnitude lower than that of ATRA, 72 h after its addition to the cell culture medium. Since angiogenesis is important for the growth of hematological malignancies, we furthermore studied the effect of ATRA and its analogs on the formation of new capillaries in the in vivo chicken embryo chorioallantoic membrane (CAM). ATRA, EA-136 and EA-137 induced angiogenesis in the CAM, increased the layer of CAM keratinocytes, and resulted in a significant degree of extravasation. EA-4 had no effect on either angiogenesis or tissue structure in general. It seems that the retinoid EA-4 is a promising agent for the inhibition of human leukemia cell growth.
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PMID:Effects of retinoic acid steroidal analogs on human leukemic HL60 cell proliferation in vitro and on angiogenesis in vivo. 1565 12


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