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Biomedical subjects

K Shudo

Publications and source records attributed to K Shudo.

At least 109 records · Page 6Linked to original sources
PubMed1991

Fluorescent probes for retinoic acid receptors: molecular measures for the ligand binding pocket.

Two fluorescent probes for nuclear retinoic acid receptors (RARs) have been developed, both containing a biologically active retinoid moiety and a fluorescent dansyl moiety, but differing in the length of the spacer arm connecting the two moieties. Both probes bind RARs at their retinoid-binding sites, revealing the usefulness of the compounds as fluorescent RAR probes. By measuring the specific increase of the probes' fluorescence intensity caused by the binding to RARs, the linearized length of the RAR's retinoid-binding pocket could be estimated.

Binding, Competitive↗
PubMed1991

Fluorescent and photoaffinity labeling probes for retinoic acid receptors.

A fluorescent probe for retinoid receptors (RARs) was designed and prepared. The probe consists of a retinoid moiety and a dansyl moiety, i.e., 2-[3-(5-dimethylaminonaphthalene-1-sulfonyl)- aminopropyl-1-oxy]-4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2- naphthalenyl)carboxamido]benzoic acid: DAM-3. DAM-3 specifically bound RARs. Additionally, a photoreactive RAR fluorescent probe was designed and prepared, i.e., 2-[3-(5-azidonaphthalene- 1-sulfonyl)aminopropyl-1-oxy]-4-[(5,6,7,8-tetrahydro-5,5,8,8- tetramethyl-2-naphthalenyl)carboxamido]benzoic acid (ADAM-3). ADAM-3 irreversibly and specifically bound RARs using ultraviolet irradiation.

Affinity Labels↗
PubMed1991

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.

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.

Carcinogens↗
PubMed1991

Retinoids and their nuclear receptors.

Retinoids (retinoic acid and its biofunctional analogs) are widely involved in the control of cell proliferation, cell differentiation, and embryogenic development. A series of novel synthetic retinoids (called retinobenzoic acids), which include retinoid antagonists, have been developed and have been shown to be useful tools to investigate retinoidal action molecular mechanisms. Retinoids elicit their biological effects by binding to specific nuclear receptors (RARs) belonging to a steroid/thyroid nuclear receptor superfamily. RARs act as retinoid-dependent transcription factors which bind to a specific gene site and control the gene's expression. The diversity of retinoidal actions can possibly be interpreted by considering the following characteristics, all of which are quite diversified: the structure and spatial/temporal distribution of RARs, the base sequences which interact with RARs, the cell type specifically determined hierarchy of gene expression, and the nuclear coregulators which interact with RARs. Abnormality of an RAR gene which might cause acute promyelocytic leukemia is also discussed.

Animals↗
PubMed1991

[Retinoids and acute promyelocytic leukemia].

Retinoic acid and its analogs, retinoids, have been shown to be useful in the treatment of several types of tumors. Retinoids elicit their biological activities by binding to their specific nuclear receptors, denoted as RAR-alpha, beta and gamma. RAR's have been established to be retinoid-dependent transcription factors which belong to the steroid/thyroid nuclear receptor superfamily. Recently, retinoic acid has been reported to be extremely effective in the treatment of acute promyelocytic leukemia (APL) giving more than 70% complete remission efficiency. APL has been characterized by the specific chromosomal translocation, t(15;17). Analysis of the t(15;17) breaking point revealed that (i) either RAR-alpha on chromosome 17 or the gene named myl on chromosome 15 is abnormal in APL cells, and (ii) the abnormal fused protein myl/RAR-alpha is expressed, which is suspected to cause the APL. Thus, RAR-alpha gene may be now regarded as one of tumor suppressor genes.

Animals↗
PubMed1991

Retinoids and their nuclear receptors.

Retinoids (retinoic acid and its biofunctional analogs) are widely involved in the control of cell proliferation, cell differentiation, and embryogenic development. A series of novel synthetic retinoids (called retinobenzoic acids), which include retinoid antagonists, have been developed and have been shown to be useful tools to investigate retinoidal action molecular mechanisms. Retinoids elicit their biological effects by binding to specific nuclear receptors (RARs) belonging to a steroid/thyroid nuclear receptor superfamily. RARs act as retinoid-dependent transcription factors which bind to a specific gene site and control the gene's expression. The diversity of retinoidal actions can possibly be interpreted by considering the following characteristics, all of which are quite diversified: the structure and spatial/temporal distribution of RARs, the base sequences which interact with RARs, the cell type specifically determined hierarchy of gene expression, and the nuclear coregulators which interact with RARs. Abnormality of an RAR gene which might cause acute promyelocytic leukemia is also discussed.

Amino Acid Sequence↗
PubMed1991

Enantio- and meso-oligodeoxyribonucleotides.

As sugar-modified oligodeoxyribonucleotides, L-homooligomers (L-dA12 and L-dT12) and a L/D-alternative oligomer ((L-dA-D-dA)6) were synthesized. These oligomers were quite resistant towards phosphodiesterase degradations. L-dA12 formed complexes with poly(dT) and poly(U) at 0 degree C with different stabilities, on the other hand L-dT12 did not show obvious hypochromicities after mixing with complementary natural homopolymers. An alternative sequence, (L-dA-D-dA)6, interacted with both type homopolymers and stabilities of the complexes increased compared to that of L-dA12.

Oligodeoxyribonucleotides↗
PubMed1990

Cytosolic-nuclear tumor promoter-specific binding protein (CN-TPBP) in human promyelocytic leukemia cells HL-60.

12-O-Tetradecanoylphorbol 13-acetate (TPA) is a potent tumor promoter and is known to induce terminal differentiation of human promyelocytic leukemia cells HL-60 to mature monocytes. To investigate the molecular mechanism of TPA actions, TPA-specific binding proteins in HL-60 were analyzed. Anion exchange high-performance liquid chromatography revealed that HL-60 cells possess TPA-specific binding proteins other than protein kinase C (PKC). One of these TPA-specific binding proteins exists in the cytosolic fraction of HL-60 cells, but translocates into the nuclear fraction of HL-60 cells after the treatment of the cells with TPA. The results suggest that HL-60 cells take up TPA into the nuclei via the TPA-specific binding protein. The TPA-specific binding protein binds TPA, phorbol 12,13-di-butylate, teleocidin B-2, teleocidin B-3, and debromoaplysiatoxin in a mutually competitive manner. However, the protein does not bind to okadaic acid, olivoretin C, retinoic acid, or dioxin. This cytosolic-nuclear tumor promoter-specific binding protein (CN-TPBP) might play an essential role in the action of tumor promoters.

Binding, Competitive↗
PubMed1990

Expression of retinoic acid receptor genes and the ligand-binding selectivity of retinoic acid receptors (RAR's).

Retinoids of a structurally new type, 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenylcarbamoyl)benzoic acid (Am80) and (E)-4-[3-(3,5-di-tert-butylphenyl)-3-oxo-1-propenyl]-benzoic acid (Ch55), were used for the investigation of retinoid receptors in some human cell lines. Previously, using these retinoids, we have established that HL-60 cells possess two retinoid receptors, RAR-alpha and RAR-beta. In this paper, we report coexpression of RAR-alpha- and RAR-beta-genes established by Northern analysis. Further, the binding selectivity of the RAR products toward all-trans-retinoic acid (RA), Am80 and Ch55 was studied by filter binding assay. The affinity of the ligands toward RAR-alpha decreased in the order of Ch55 greater than RA greater than Am80. The affinity of the ligands toward RAR-beta decreased in the order of Ch55 greater than Am80 greater than RA.

Blotting, Northern↗
PubMed1990

Synthetic retinoids, retinobenzoic acids, Am80, Am580 and Ch55 regulate morphogenesis in chick limb bud.

The retinobenzoic acids Am80, Am580 and Ch55 are synthetic stable analogs of retinoic acid (RA), and show very strong differentiation-inducing activity in human myelogeneous leukemia cell line HL-60. To examine the effects of these synthetic retinoids on limb pattern formation, AG1-X2 beads containing these retinoids were applied to the anterior margin of stage 19-20 chick wing buds. By implanting the beads with 1 microgram/ml retinoids, normal wings were formed and extra digits 2 or 32 were rarely formed. As the retinoid concentrations increased from 10 micrograms/ml to 100 micrograms/ml duplicated limbs 3234, 43234, 432234, 4334 were progressively produced. At higher concentrations, 1 mg/ml, the wings often truncated, although duplication occurred in some embryos. These synthetic analogs seem to have the same degree of morphogenetic potential as RA, since the activity index of these retinoids was similar to that of RA. Since these synthetic retinoids hardly bind to CRABP (cellular retinoic acid-binding protein), it may be possible that the retinoids and RA may affect limb-pattern formation without the interaction with CRABP. It is known that limb buds cannot develop distal structures when the posterior region including all ZPA (zone of polarizing activity) is removed. When beads containing the above mentioned retinoids were implanted to the anterior margin of wing buds from which the posterior one third region including all ZPA had been removed, distal growth of the wing buds and the formation of digit elements were observed. Some of the wing buds produced a completely reverse digit pattern 432. From these results, we discussed the roles of RA in limb development and pattern formation.

Animals↗
PubMed1990

Retinobenzoic acids. 5. Retinoidal activities of compounds having a trimethylsilyl or trimethylgermyl group(s) in human promyelocytic leukemia cells HL-60.

The retinoidal activities of trimethylsilyl or trimethylgermyl-containing retinobenzoic acids are discussed on the basis of differentiation-inducing activity on human promyelocytic leukemia cells HL-60. Compounds with a trimethylsilyl or trimethylgermyl group at the meta position of the generic formula 2 have more potent activities than the corresponding retinobenzoic acids with a m-tert-butyl group. Compounds having two m-trimethylsilyl or -trimethylgermyl groups also have strong activities, and (E)-4-[3-[3,5-bis(trimethylsilyl)phenyl]-3-oxo-1-propenyl]benzoic acid (22, Ch55S) and (E)-4-[3-[3,5-bis(trimethylgermyl)phenyl]-3-oxo-1- propenyl]benzoic acid (35, Ch55G) are more active than retinoic acid by 1 order of magnitude. However, in the para-substituted chalcone derivatives, the replacement of a tert-butyl group (49, Ch40) with a trimethylsilyl (27, Ch40S) or a trimethylgermyl (30, Ch40G) group caused the disappearance of the activity.

Antineoplastic Agents↗
PubMed1990

Expression of nuclear retinoic acid receptors in wild-type and mutant embryonal carcinoma PCC4.aza1R cells.

Retinoic acid (RA) induces differentiation of murine embryonal carcinoma PCC4.aza1R cells. In this study, the expression of nuclear retinoic acid receptors (RARs) in PCC4.aza1R cells is examined. Analyses of [3H]RA-labeled nuclear extracts prepared from PCC4.aza1R cells by size-exclusion high-performance liquid chromatography demonstrated the presence of a specific RA-binding activity that migrated with a molecular weight of approximately 50,000. More than 95% of this binding activity was associated with the nuclear fraction. In contrast to cytosolic retinoic acid-binding protein, the RARs bound RA analogues of the Ch-series very effectively. Northern blot analyses of total RNA with complementary DNA probes specific for RAR alpha, RAR beta, and RAR gamma showed that PCC4.aza1R cells contain predominantly transcripts encoding RAR alpha and RAR gamma; RAR beta transcripts were undetectable. Treatment of PCC4.aza1R cells with RA increased the levels of RAR beta mRNA in a dose- and time-dependent manner. The RA concentration for half-maximum induction of RAR beta mRNA was 1 nM. An increase in RAR beta mRNA was detectable as early as 2 h after the addition of RA. This increase was not abrogated by cycloheximide, suggesting that protein synthesis is not required for this response. The ability of several retinoids to increase RAR beta mRNA levels in PCC4.aza1R cells correlated well with their binding affinity to the RARs but not with their binding affinity to cytosolic retinoic acid-binding protein. Two mutant cell lines, PCC4(RA)-1 and (RA)-2, which do not undergo differentiation after RA treatment, contained levels of RAR-binding activity very similar to those of the parental cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Enantio-oligodeoxyribonucleotides.

As a sugar-modified oligonucleotide, a hexamer of 9-(2-deoxy-beta-L-erythro-pentafuranosyl)-9H-purin-6-amine, [L-(dAp)5dA], was synthesized by triester method. The L-hexamer was resistant to bovine spleen phosphodiesterase. UV absorption studies indicated that L-hexamer formed a complex with poly U but not with poly dT at 0 degrees C. It was assumed that enantio-DNA's possese the ability to distinguish complementary RNA from DNA.

Adenine Nucleotides↗
PubMed1989

A highly potent antiangiogenic activity of retinoids.

Four retinoids, i.e. retinol (vitamin A), retinoic acid, retinyl acetate and synthetic chalcone carboxylic acid (Ch 55), were examined for their effects on embryonic angiogenesis using 4.5-day chorioallantoic membranes of chick embryo. The effects of these retinoids were compared with that of antibiotic herbimycin A, which was the most powerful inhibitor of the angiogenesis reported previously. The four retinoids strongly inhibited embryonic angiogenesis; the order of inhibitory activity was Ch 55 greater than retinoic acid greater than herbimycin A greater than retinyl acetate based on the dose required for the half-maximal inhibitory effect. The present results suggest that retinoids are effective inhibitors of angiogenesis, and can be applied for the management of certain diseases accompanied by aberrant angiogenesis, particularly that which occurs during progressive growth of solid tumors.

Animals↗
PubMed1989

Zinc ion enhances the blocking potency of synthetic analogs of spider toxin (JSTX) on the glutamate receptor.

The effect of synthetic spider toxin analogs containing aza-crown in combination with zinc and copper was studied on the lobster neuromuscular synapse. The suppressive action of N4-type spider toxin analog (N4) on excitatory postsynaptic potentials (EPSPs) was markedly enhanced in the presence of 10(-5)-10(-4) M Zn2+. Cu2+ (10(-4) M) also had a potentiating effect on the suppression of EPSPs by N4 but to a lesser degree than Zn2+. While N6-type spider toxin analog (N6) suppressed EPSPs more effectively than N4, additional suppression was not pronounced in the presence of Zn2+ or Cu2+. The results suggest that chelatable divalent metal ions play an important role in the blocking mechanism of glutamate receptor by the spider toxin.

Action Potentials↗
PubMed1989

Retinobenzoic acids. 2. Structure-activity relationships of chalcone-4-carboxylic acids and flavone-4'-carboxylic acids.

The structure-activity relationships of (E)-chalcone-4-carboxylic acids, which are retinoidal benzoic acids represented by R-Ph-X-Ph-COOH (4, X = -COCH = CH-), are discussed on the basis of differentiation-inducing activity on human promyelocytic leukemia cells HL-60. The activity was increased by the substitution of a bulky alkyl group(s) (R), and among such compounds, (E)-4-[3-(3,5-di-tert-butylphenyl)-3-oxo-1-propenyl]benzoic acid (Ch55) and (E)-4-[3-oxo-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1 -propenyl]benzoic acid (Ch80) are several times more active than retinoic acid. Though the stable conformer of chalcone derivatives is linear (s-cis form), the conformationally restricted analogue 4-(6,7,8,9-tetrahydro-6,6,9,9-tetramethyl-4H-4-oxonaphtho[2,3-b]py ran-2-yl)benzoic acid (Fv80) is more active than Ch80. While the effect of introduction of an oxygen atom varied, 4-[1-hydroxy-3-oxo-3-(5,6,7,8-tetrahydro-3-hydroxy-5,5,8,8-tetramethyl-2 - naphthalenyl)-1-propenyl]benzoic acid (Re80), regarded as a derivative of Ch80 with two additional hydroxyl groups, has very strong activity.

Carboxylic Acids↗
PubMed1989

Retinobenzoic acids. 3. Structure-activity relationships of retinoidal azobenzene-4-carboxylic acids and stilbene-4-carboxylic acids.

Alkyl-substituted azobenzene-4-carboxylic acids are potent differentiation inducers of human promyelocytic leukemia cell line HL-60 to mature granulocytes. Their structure-activity relationships are very similar to those of other retinoidal benzoic acids which are generally represented by 4 and named retinobenzoic acids. The structure-activity relationships of azobenzenecarboxylic acids can also be applied to the known retinoid TTNPB (3). Thus, (E)-4-[2-(3,4-diisopropylphenyl)-1-propenyl]benzoic acid (St30 (28] and (E)-4-[2-(3-tert-butylphenyl)ethenyl]benzoic acid (St40 (29], the acyclic alkyl analogues of TTNPB, are nearly as active as retinoic acid. Among the oxidatively derived compounds (Az90, Ep series and Ox series) of azobenzene- or stilbenecarboxylic acids, Az90 (71) and Ep80 (61) have strong activities. However, all the bishydroxylated derivatives of TTNPB are inactive, while a diketo analogue Ox580 (69) has only weak potency. The activities of conformationally restricted compounds of TTNPB offer some information on the stereochemistry of the active form of these retinoidal compounds.

Benzoates↗