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) is a vitamin A derivative with striking effects on development and cell differentiation. The identification of three RA receptors (RAR alpha, beta and gamma) as members of the nuclear receptor superfamily led to important insights into the molecular mechanism of action of retinoids. The nuclear receptors, that also include receptors for steroid hormone, vitamin D3 and thyroid hormone act as ligand-inducible transcription factors and are characterized by the presence of two well conserved DNA- and hormone-binding domains. One of the most intriguing properties of RA is its ability to induce in vivo differentiation of acute promyelocytic leukaemia (APL) cells into mature granulocytes, leading to morphological complete remissions. We and others have shown that the t(15;17) translocation specifically associated with APL fuses an as yet unidentified gene, named PML, to the retinoic acid receptor alpha locus. The resulting PML-RAR alpha hybrid protein that retains most of the functional domains of parental proteins exhibits altered transactivating functions when compared to the wild-type receptor; however the biological significance of this property in the transforming phenotype is still obscure. PML, whose function is unknown, belongs to a novel family of nuclear proteins characterized by the presence of a Cys/His-rich motif, named a RING finger, that include RNA-binding proteins, transcription factors and oncoproteins. A dimerization domain within PML is able to mediate the formation of PML-RAR alpha homodimers that can bind to target sequences with distinct DNA binding properties if compared with RAR alpha.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The t(15;17) translocation in acute promyelocytic leukemia. 767 45

The retinoid receptors belong to a large superfamily of ligand-inducible transcription factors that include the steroid, vitamin D and thyroid hormone receptors, the peroxisome proliferator-activated receptor, the insect edysteroid receptor, and a number of orphan receptors whose ligands are unknown. All nuclear receptors have several well-characterized structural domains, including a conserved DNA-binding domain, and a ligand binding domain at the carboxyl terminus of the receptor. The RAR and RXR classes of nuclear retinoic acid receptors are each composed of alpha, beta and gamma subtypes with more than one isoform for each receptor subtype. Data from many investigators suggest there are RAR- and RXR-dependent gene pathways, and that the individual receptor subtypes may control distinct gene expression patterns. In addition, RXR has been found to heterodimerize with other nuclear receptors to form active transcriptional complexes, which influence the activity of a variety of gene pathways important in growth and differentiation. As a result, retinoids have been useful clinical agents in Dermatology and Oncology. However, upon prolonged exposure to retinoic acid, resistance to retinoids has often been encountered both in the clinical setting and in long-term cell culture (HL60R and RAC65 cells). In the latter case, retinoid resistance has been associated with a mutation in the RAR gene which transcribes a RAR receptor truncated at the C-terminal end. These mutated RAR receptors exhibit a reduced affinity for retinoic acid while retaining the ability to bind to a retinoic acid response element on DNA. As a result, these mutant receptors exhibit dominant-negative activity by binding to the DNA without activating transcription and by competing with other receptors for sites on the response element. In fact, dominant-negative activity may be very important in the development of many neoplastic diseases, including acute promyelocytic leukemia (APL), where a t(15;17) chromosomal translocation fuses the PML gene to the RAR gene, to produce a PML-RAR fusion protein in large excess in the cell. However, retinoid resistance in the patient is most probably the result of pharmacokinetic problems, whereby, with continuous retinoid treatment, the plasma levels of retinoic acid gradually decrease to below that required to maintain differentiation of leukemic cells in vivo. A major challenge for drug discovery is to design a drug which circumvents these pharmacokinetic problems either by designing novel drug delivery systems or by employing retinoids which do not bind to CRABP, such as 9-c-RA.(ABSTRACT TRUNCATED AT 400 WORDS)
Leukemia 1994
PMID:The retinoid receptors. 780 17

The retinoid receptors belong to a large superfamily of ligand-inducible transcription factors that include the steroid, vitamin D and thyroid hormone receptors, the peroxisome proliferator-activated receptor, the insect edysteroid receptor, and a number of orphan receptors whose ligands are unknown. All nuclear receptors have several well-characterized structural domains, including a conserved DNA-binding domain, and a ligand binding domain at the carboxyl terminus of the receptor. The RAR and RXR classes of nuclear retinoic acid receptors are each composed of alpha, beta and gamma subtypes with more than one isoform for each receptor subtype. Data from many investigators suggest there are RAR- and RXR-dependent gene pathways, and that the individual receptor subtypes may control distinct gene expression patterns. In addition, RXR has been found to heterodimerize with other nuclear receptors to form active transcriptional complexes, which influence the activity of a variety of gene pathways important in growth and differentiation. As a result, retinoids have been useful clinical agents in Dermatology and Oncology. However, upon prolonged exposure to retinoic acid, resistance to retinoids has often been encountered both in the clinical setting and in long-term cell culture (HL60R and RAC65 cells). In the latter case, retinoid resistance has been associated with a mutation in the RAR gene which transcribes a RAR receptor truncated at the C-terminal end. These mutated RAR receptors exhibit a reduced affinity for retinoic acid while retaining the ability to bind to a retinoic acid response element on DNA. As a result, these mutant receptors exhibit dominant-negative activity by binding to the DNA without activating transcription and by competing with other receptors for sites on the response element. In fact, dominant-negative activity may be very important in the development of many neoplastic diseases, including acute promyelocytic leukemia (APL), where a t(15;17) chromosomal translocation fuses the PML gene to the RAR gene, to produce a PML-RAR fusion protein in large excess in the cell. However, retinoid resistance in the patient is most probably the result of pharmacokinetic problems, whereby, with continuous retinoid treatment, the plasma levels of retinoic acid gradually decrease to below that required to maintain differentiation of leukemic cells in vivo. A major challenge for drug discovery is to design a drug which circumvents these pharmacokinetic problems either by designing novel drug delivery systems or by employing retinoids which do not bind to CRABP, such as 9-c-RA.(ABSTRACT TRUNCATED AT 400 WORDS)
Leukemia 1994 Nov
PMID:The retinoid receptors. 796 25

Iodothyronine 5'-deiodinase isoenzymes generate the thyroid hormone 3,3',5-triiodothyronine from the prohormone L-T4. Basal and retinoic acid (RA)-induced type I 5'-deiodinase (5'DI) activities were studied in human thyroid carcinoma cell lines. In the follicular thyroid carcinoma line FTC-133, nanomolar concentrations of 9-cis, 13-cis-, and all-trans-RA induced 5'DI activity. Kinetics with all-trans-RA revealed 5'DI stimulation after 1 day and a maximal effect after 3 days. Increased abundance of the p27 5'DI subunit was demonstrated after RA treatment by N-bromoacetyl-[125I]T4 affinity labeling. Actinomycin-D and cycloheximide blocked RA-mediated induction. RA stimulated 5'DI activity to a lesser extent in FTC-238 cells, whereas neither basal 5'DI activity nor stimulation by RA was found in anaplastic thyroid carcinoma, human lung, or leukemia cell lines. Steady state messenger ribonucleic acid levels of RA receptor-alpha and -beta were increased after incubation of FTC-133 cells with all-trans-RA. The high 5'DI activity of differentiated rat thyroid FRTL-5 cells was not further induced by RA. Butyrate did not alter 5'DI, but increased the activity of the differentiation marker alkaline phosphatase in FTC-133 and FTC-238 cells. T4 and T3 had no effect on basal or RA-stimulated 5'DI activity. These data suggest that expression and retinoid induction of 5'DI may serve as a sensitive and functional differentiation parameter of follicular thyroid carcinoma cells.
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PMID:Retinoids stimulate type I iodothyronine 5'-deiodinase activity in human follicular thyroid carcinoma cell lines. 807 63

Regulation of gene expression in response to steroids, thyroid hormone, and retinoids is mediated by an impressive array of intracellular receptors. Sequence analysis showed that the hormone receptors comprise a large superfamily of ligand-responsive transcription factors. Upon binding to hormones, the receptors interact with specific hormone response elements located in the promoters of numerous genes. Promoter-bound receptors communicate with distinct receptors and/or additional members of the transcriptional machinery, frequently evoking protein-protein interactions. Ultimately, this results in the induction of complex gene systems that control hormone-induced processes such as differentiation, cell growth, and homeostasis. In addition to the genes transcribed by RNA polymerase II, the lipophilic hormones, particularly glucocorticoids, can also modulate RNA polymerase I-directed transcription of the ribosomal gene. For both transcription systems, activation and repression of genes in response to hormones have been reported. Finally, the involvement of hormone receptors in tumorigenesis has been discussed. It is likely that receptor studies will have major implications in the diagnosis and therapy of diseases such as leukemia.
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PMID:Control of gene expression by lipophilic hormones. 838 39

We reported HTLV-1 uveitis (HU) as the third distinct clinical entity associated with HTLV-1 infection. Uveitis has advantages for studying the pathogenetic mechanisms of inflammatory diseases caused by HTLV-1, since observation of the disease process is relatively easy and clinical samples from the lesion can be obtained. Results of our clinical, virological and epidemiological studies of HU patients will be first summarized. Then we present results on in vitro studies that showed transactivation of HTLV-1 LTR by thyroid hormone and discuss the significance in the context of pathogenesis of HTLV-1-related inflammatory diseases.
Leukemia 1997 Apr
PMID:HTLV-1 uveitis (HU). 920 60

Although retinoic acid (RA) has been known for many years to be a modulating agent that plays a role in generating both granulocytes and monocytes, the molecular mechanism underlying this role has not been defined in the monoblast lineage. In particular, the part played by the retinoid X receptors (RXRs), which are members of the steroid/thyroid hormone nuclear receptor family, has not been explored. In this study, therefore, the human monoblastic leukemia cell line U937 has been used as a model system to investigate the role of one of the RXRs, RXR-alpha, in monoblast differentiation. RXR-alpha mRNA was present in untreated U937 cells, and levels increased after induction of differentiation with phorbol ester. The same was found for RXR-beta mRNA. Using plasmids containing sense or antisense RXR-alpha sequences under the control of an inducible promoter, we generated stably transfected cell lines which expressed either increased or decreased levels of RXR-alpha, respectively. The sense cell lines (U alpha S and its clonal derivative alpha G2S) showed increased sensitivity to RA, while the antisense cell lines (U alpha A and its clonal derivative alpha B5A) showed decreased sensitivity to RA, as demonstrated by growth inhibition and by regulation of an RA-responsive reporter gene. Both U alpha A and alpha B5A also failed to respond to another modulating agent, 1 alpha,25-dihydroxycholecalciferol (DHCC), but only U alpha S and not alpha G2S showed an enhanced response to DHCC. The combination of RA and DHCC together inhibited growth of both sense and antisense cell lines. In addition, alpha G2S exhibited increased expression of CD11b and CD54, while alpha B5A cells showed increased expression of CD102, suggesting that RXR-alpha has a role in regulating expression of cell adhesion molecules in U937 cells. These results demonstrate that RXR-alpha has a role in mediating growth inhibition and cell adhesion during myelomonocytic differentiation, and suggest that different species of heterodimers involving RXR-alpha may control the acquisition of different features of mature monocyte/macrophage function.
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PMID:Stable transfection of U937 cells with sense or antisense RXR-alpha cDNA suggests a role for RXR-alpha in the control of monoblastic differentiation induced by retinoic acid and vitamin D. 934 89

Cytosol and nuclei of Lewis lung carcinoma (LLC) cells contain high affinity binding sites specific for the arachidonic acid metabolite 12(S)-hydroxy-5,8,10,14-eicosatetraenoic acid (12(S)-HETE). In this report we present evidence that the cytosolic 12(S)-HETE binding complex also occurs in human erythroleukemia (HEL) and promonocytic leukemia (U937) cells as well as in murine 3T3-L1 preadipocytes but not in intestinal epithelial cells (Int407). The cytosolic 650 kDa 12(S)-HETE-binding complex was found to consist of subunits; raising the ATP concentration in cytosol led to conversion of the 650 kDa complex to a 50 kDa binding component, presumably the actual 12(S)-HETE binding polypeptide. Lowering of the cytosolic concentration of ATP had the opposite effect, i.e., the amount of the 650 kDa complex increased. Another subunit of the 650 kDa complex was identified as heat shock protein 70 (hsp70) by Western blot analyses and coimmunoprecipitation. Hsp70 was present in substoichiometric amounts, in an approximate 1:6 ratio. The multimeric nature of the binding complex and the identification of hsp70 as a subunit suggest that there are similarities between the 12(S)-HETE binding protein and receptors of the steroid/thyroid hormone superfamily.
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PMID:Identification of subunits of the 650 kDa 12(S)-HETE binding complex in carcinoma cells. 950 84

Retinoic acid (RA) activated the extracellular signal-regulated kinase (ERK) 2 mitogen-activated protein kinase (MAPK) of HL-60 human myeloblastic leukemia cells before causing myeloid differentiation and cell cycle arrest associated with hypophosphorylation of the retinoblastoma (RB) tumor suppressor protein. ERK2 activation by mitogen-activated protein/ERK kinase (MEK) was necessary for RA-induced differentiation in studies using PD98059 to block MEK phosphorylation. G0 growth arrest and RB tumor suppressor protein hypophosphorylation (which is typically associated with induced differentiation and G0 arrest), two putatively RB-regulated processes, also depended on ERK2 activation by MEK. Activation of ERK2 by RA occurred within hours and persisted until the onset of RB hypophosphorylation, differentiation, and arrest. ERK2 activation was probably needed early, because delaying the addition of PD98059 relative to that of RA restored most of the RA-induced cellular response. In contrast to RA (which activates RA receptors (RARs) and retinoid X receptors in HL-60 cells with its metabolite retinoids), a retinoid that selectively binds RAR-gamma, which is not expressed in HL-60 cells, was relatively ineffective in causing ERK2 activation. This is consistent with the need for a nuclear retinoid receptor function in RA-induced ERK2 activation. RA reduced the amount of unphosphorylated RAR-alpha, whose activation is necessary for RA-induced differentiation and arrest. This shifted the ratio of phosphorylated:unphosphorylated RAR-alpha to predominantly the phosphorylated form. Unlike other steroid thyroid hormone receptors susceptible to phosphorylation and activation by MAPKs, RAR-alpha was not phosphorylated by the activated ERK2 MAPK. The results thus show that RA augments MEK-dependent ERK2 activation that is needed for subsequent RB hypophosphorylation, cell differentiation, and G0 arrest. The process seems to be nuclear receptor dependent and an early seminal component of RA signaling causing differentiation and growth arrest.
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PMID:Retinoic acid induced mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase-dependent MAP kinase activation needed to elicit HL-60 cell differentiation and growth arrest. 967 85

To determine how often central hypothyroidism remains undetected by routine out-patient tests of thyroid hormone, we studied 208 pediatric cancer survivors referred for evaluation because of signs of subtle hypothyroidism or hypopituitarism. Of the 208 (68 females and 140 males), 110 had brain tumors, 14 had other head/neck tumors, 11 had solid tumors remote from head and neck, and 73 had leukemia. Patients were evaluated 1-16 yr (mean, 6.1+/-4.1 yr) after tumor diagnosis. The nocturnal TSH surge and response to TRH were measured. Of 160 patients with free T4 in lowest third of normal, 34% had central hypothyroidism (blunted TSH surge or low/delayed TSH peak or delayed TSH decline after TRH); 9% had central hypothyroidism with mild TSH elevation (mixed hypothyroidism). Another 16% had mild primary hypothyroidism (TSH, 5-15 mU/L). Of 48 with free T4 in the upper two thirds of normal, 14% had central hypothyroidism; 17% had mild primary hypothyroidism. Incidence of central, mixed, and mild primary hypothyroidism 10 yr after tumor diagnosis was significantly related to total cranial radiation dose (P < 0.0001). Of 62 patients with central hypothyroidism, 34% had not developed GH deficiency. TSH surge identified 71%, and response to TRH identified 60% of those with central hypothyroidism. More than half of the slowly growing patients who have received cranial or craniospinal radiation for childhood cancer develop subtle hypothyroidism. In our study group, 92% of patients with central hypothyroidism and 27% with mixed hypothyroidism would have remained undiagnosed using baseline thyroid function tests alone. Both TSH surge and response to TRH must be evaluated to identify all of these patients.
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PMID:Diagnosis of hidden central hypothyroidism in survivors of childhood cancer. 1059 5


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