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

Since initial studies identifying the important role of vitamin A and its derivatives (retinoids) in maintaining the integrity of epithelial tissues, these compounds have served as paradigms for experimental studies exploring the pharmacologic modification of carcinogenesis. Retinoids have clearly been shown to inhibit chemically induced mammary and urothelial carcinogenesis in experimental animals. Prohibitive toxicity of the parent compound, vitamin A, led to a systematic search for synthetic derivatives with an improved therapeutic index. More than 1500 such compounds have been synthesized, many retaining chemopreventive potential, but with less toxicity. Although several anecdotal reports confirming therapeutic benefits of cis-retinoic acid in patients with acute promyelocytic leukemia and myelodysplastic syndromes appeared in the late 1970s and early 1980s, the remarkable studies of Huang and his colleagues in China in 1988 reporting complete remissions in patients with this uncommon variety of acute myelogenous leukemia with the transisomer of retinoic acid (all-trans-retinoic acid) led to a resurgence of interest in the retinoids as differentiating agents for the prevention and therapy of cancer. Furthermore, molecular studies showing DNA rearrangements of the alpha nuclear receptor for retinoic acid located on chromosome 17 in patients with acute promyelocytic leukemia, a disease invariably associated with a translocation between chromosomes 15 and 17, provided a direct connection between an altered nuclear receptor and the development of a human malignancy. The retinoids also may have important beneficial effects in prevention of recurrent malignancies once the primary tumor has been treated, such as in squamous cell carcinoma of the head and neck. Because retinoids appear to be less effective in inducing differentiation in nonpromyelocytic leukemia cells, investigators have conducted a number of studies to exploit potential synergism between retinoids and other differentiating agents or biologic effectors. Differentiation therapy and chemoprevention are attractive alternative approaches to intensive cytotoxic chemotherapy. It is now clear that retinoids represent one class of compounds with which it may be possible to reverse the progression of malignant disease and prevent carcinogenesis.
 ...
PMID:Retinoids in cancer treatment. 144 94

ELP, the embryonal LTR binding protein, is a member of the nuclear receptor superfamily and a mouse homologue of Drosophila FTZ-F1. ELP is expressed specifically in undifferentiated mouse embryonal carcinoma cells and participates in suppression of the Moloney murine leukemia virus genome. The zinc finger domain of the protein was fused with glutathione S-transferase and was successfully used for isolating genomic targets. Sixteen genomic fragments were isolated and twelve of them strongly interacted with ELP. Six of the ELP binding fragments were analyzed further. All of these contained the multiple binding sites for ELP, which matched well with the consensus binding sequence for FTZ-F1, YCAAGGYCR. Among these, three fragments functioned as negative regulatory elements in response to ELP, when placed upstream to the promoter region of the Moloney leukemia virus. These results indicate that ELP may function as a negative transcription factor for a variety of cellular sequences, in addition to suppressing expression of Moloney leukemia virus in early embryonal cells. It was also shown that the procedure employed here works well for isolation of genomic targets of transcription factors.
 ...
PMID:Isolation of high affinity cellular targets of the embryonal LTR binding protein, an undifferentiated embryonal carcinoma cell-specific repressor of Moloney leukemia virus. 157 38

The past year has seen important advances in our understanding of the molecular biology of human cancer. We have learned more about how normal genes with critical functions in growth and development can induce cellular transformation and malignancy if mutated or overexpressed. The finding of such oncogenes in specific human cancers often portends a poor prognosis. We have learned more about tumor suppressor genes, whose loss by mutation, deletion, or translocation can lead to cancer. A series of defects involving both oncogenes and tumor suppressor genes has been shown to characterize the multistep development of a fully malignant colon cancer. We have new insights into the promotion of malignancy by the fused gene product resulting from the chromosomal abnormality diagnostic of one leukemia, chronic myelogenous leukemia. Recently, in acute promyelocytic leukemia, a characteristic chromosomal abnormality has been shown to result in a specific fusion of a nuclear receptor that activates transcription and a previously unknown gene. Most interestingly, a ligand for this rearranged receptor has been shown to be a novel effective treatment for the disease. This review summarizes many of these advances.
 ...
PMID:Oncogenes and clinical oncology. 164 34

The identification of the viral oncogene v-erbA carried by an avian leukemia retrovirus has directly demonstrated the involvement of hormone receptors in neoplastic transformation. v-erbA represents an altered form of a nuclear receptor of the thyroid hormone T3. It blocks the differentiation of chicken erythrocyte progenitor cells and contributes to sarcoma transformation in association with other oncogenes. The protein encoded by v-erbA behaves as an antagonist against the normal T3 receptors and retinoic acid receptors. The primary effects of the protein result in altering the transcription of genes normally under control of the intact receptors. Presumably among these target genes are to be found genes which control cell differentiation and proliferation.
 ...
PMID:[V-erbA oncogene, model of oncogenic activation of hormone receptor]. 166 30

Retinoic acid, vitamin D3, and dexamethasone are known inducers of myeloid leukemic cell differentiation. Recent evidence indicates that these drugs mediate their biological effects through binding to a nuclear receptor which belongs to the steroid/thyroid hormone receptor superfamily. This paper shows that the ligands of the other receptors of this family, estrogens, progesterone, androgens and thyroid hormone, do not induce leukemic cell differentiation. However, thyroid hormone potentiates, by one order of magnitude, the dose-response effect of retinoic acid in HL-60 cells.
Leukemia 1991 May
PMID:Stimulatory effect of thyroid hormone on RA-induced granulocytic differentiation in leukemic cells. 185 8

The activity of cytidine deaminase markedly increases during the differentiation of HL-60 cells induced by dimethylsulfoxide or 1,25-dihydroxy vitamin D3, but does not increase when the inducer is retinoic acid. Here it is demonstrated that retinoic acid inhibits the increase in cytidine deaminase activity elicited by the other two inducers. This inhibitory effect of retinoic acid (i) was not the result of a direct action on the enzymatic activity; (ii) was correlated with the differentiating effect of retinoic acid, as indicated by the similar time-course and dose-dependence of both effects, and by additional studies with various retinoids and with an HL-60 variant resistant to retinoic acid-induced differentiation; (iii) required the continued presence of the drug for more than 24 h, and could not be reversed after 48 h; (iv) was manifest, after a lag-time of 24 h, at whatever time retinoic acid was added during the 5 days of treatment of the cells with the differentiation inducers; and (v) was prevented by the addition of the protein synthesis inhibitor cycloheximide. These data indicate that retinoic acid negatively regulates the expression of cytidine deaminase in HL-60 cells, and suggest that this effect is mediated by a protein, the synthesis of which should be controlled by the nuclear receptor of retinoic acid.
Leukemia 1991 Aug
PMID:Retinoic acid inhibits the expression of cytidine deaminase linked to the differentiation of the human leukemic cell line HL-60. 188 22

Suspension-cultured HeLa cells possess a cytosolic-nuclear tumor promoter-specific binding protein (CN-TPBP) which lacks protein kinase C activity. This CN-TPBP existed in cytosol of HeLa cells, but translocated into nuclear fraction of the cells after treatment of the cells with 12-O-tetradecanoylphorbol 13-acetate (TPA). The translocation of CN-TPBP induced by TPA became apparent within 10 min after the treatment with TPA, and was completed within 3 h. CN-TPBP bound TPA with the association constant of 1.4 x 10(10) M-1, and also bound teleocidin B, debromoaplysiatoxin, and thapsigargin in a mutually competitive manner. The binding affinity order of synthetic analogs of teleocidin B correlated with the adhesion-inducing potency order of the compounds toward human leukemia cell line HL-60. The apparent molecular weight of CN-TPBP under non-denaturing conditions was estimated to be 66-68 kDa. CN-TPBP forms a complex with the 90 kDa heat shock protein, and the complex was stabilized by the presence of molybdate. These characteristics of CN-TPBP are similar to those of the nuclear receptors of glucocorticoid and dioxin. These findings suggested that CN-TPBP acts as a nuclear receptor for tumor promoters, and that tumor promoters may exert their biological effects by binding to CN-TPBP.
 ...
PMID:Cytosolic-nuclear tumor promoter-specific binding protein: association with the 90 kDa heat shock protein and translocation into nuclei by treatment with 12-O-tetradecanoylphorbol 13-acetate. 190 53

Thyroid hormone-induced changes in cardiac function have been recognized for over 150 years; however, the biochemical basis of triiodothyronine (T3) action in the heart has been intensely investigated only during the last two decades. T3-induced changes in cardiac function can result from direct or indirect T3 effects. Direct T3 effects result from T3 action in the heart itself and are mediated by nuclear or extranuclear mechanisms. Extranuclear T3 effects, which occur independent of nuclear T3 receptor binding and increases in protein synthesis, influence primarily the transport of amino acids, sugars, and calcium across the cell membrane. Nuclear T3 effects are mediated by the binding of T3 to specific nuclear receptor proteins, which results in increased transcription of T3-responsive cardiac genes. The T3 receptor is a member of the ligand-activated transcription factor family and is encoded by cellular erythroblastosis A (c-erb A) genes. The c-erb A protein is the cellular homologue of the viral erythroblastosis A (v-erb A) protein, which causes red cell leukemia in chickens. Currently, three T3-binding isoforms of the c-erb protein and two non-T3-binding nuclear proteins that exert positive and negative effects on T3-responsive cardiac genes have been identified. T3 increases the heart transcription of the myosin heavy chain (MHC) alpha gene and decreases the transcription of the MHC beta gene, leading to an increase of myosin V1 and a decrease in myosin V3 isoenzymes. Myosin V1, which is composed of two MHC alpha, has a higher myosin ATPase activity than myosin V3, which contains two MHC beta. The globular head of myosin V1, with its higher ATPase activity, leads to a more rapid movement of the globular head of myosin along the thin filament, resulting in an increased velocity of contraction. T3 also leads to an increase in the speed of diastolic relaxation, which is caused by the more efficient pumping of the calcium ATPase of the sarcoplasmic reticulum (SR). This T3 effect results from T3-induced increases in the level of the mRNA coding for the SR calcium ATPase protein, leading to an increased number of calcium ATPase pump units in the SR. Overall, thyroid hormone leads to an increase in ATP consumption in the heart. In addition, less chemical energy of ATP is used for contractile purposes and more of it goes toward heat production, which causes a decreased efficiency of the contractile process in the hyperthyroid heart.
 ...
PMID:Biochemical basis of thyroid hormone action in the heart. 218 6

Retinoic acid (RA) has been shown to increase differentiation in some leukemia cell lines (HL-60 and KG-1) but not others (K562). Similarly, RA has been reported to have variable effects on fresh blast cells. Recently, molecular clones have been obtained for the nuclear receptor for retinoic acid. The experiments described in this paper were designed to compare expression of the receptor to biological activity in myeloblastic leukemia cells. In four continuous AML cell lines, a positive correlation was found between retinoic acid receptor (RAR) expression by Northern analysis or RNA dot blot and the ability of RA to inhibit colony formation. Kinetic studies of the most sensitive cell line showed that inhibition of colony formation was associated with reduced blast cell self-renewal and differentiation-like events. RAR was detected in freshly obtained blast cells from 23 AML patients. Patient-to-patient variation was observed; however, a correlation was not found between RAR expression and response of the freshly obtained blast cells to RA.
Leukemia 1989 Apr
PMID:Expression of a retinoic acid receptor gene in myeloid leukemia cells. 253 84

Specific [3H]retinoic acid (RA)-binding sites in nuclear and cytosolic extracts prepared from human myeloblastic leukemia HL-60 cells have been detected by sucrose density gradient sedimentation and size-exclusion high-performance liquid chromatography (HPLC) analyses. This RA-binding activity migrated as a single peak with an apparent molecular weight of 50,000 and greater than 95% of the total binding activity was associated with the nuclear extract. Nuclear extracts prepared from COS-1 cells transfected with an expression vector for the nuclear RA receptors RAR alpha or RAR beta were enriched (20- to 100-fold) with a RA-binding activity that coeluted by size-exclusion HPLC with the putative RAR from HL-60 cells. The HL-60 nuclear receptor exhibited high-affinity binding of RA and its benzoic acid analogs Ch55, Ch30, Ro 13-7410, and SRI 6409-40 and low-affinity binding of retinol, Ro 8-8717, and SRI 5442-60, correlating well with the biological activity of these compounds in HL-60 cells. Saturation binding and Scatchard plot analyses of the binding of RA to the nuclear HL-60 receptor yielded an apparent dissociation constant of approximately 0.46 nM and 1400 +/- 100 receptor sites per cell. Northern blot analyses of poly(A)+ RNA with cDNA probes specific for RAR alpha and RAR beta indicated that HL-60 cells contain predominantly transcripts encoded by the RAR alpha gene. Our results suggest that the observed nuclear RA-binding activity in HL-60 cells might mediate the action of RA in these cells.
 ...
PMID:Identification and characterization of nuclear retinoic acid-binding activity in human myeloblastic leukemia HL-60 cells. 254 90


1 2 3 4 5 6 7 8 9 10 Next >>