Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The isozyme-selectivity of chloramphenicol as an inhibitor of rat liver cytochromes P-450 has been investigated. Untreated rats and rats treated with the inducers phenobarbital, beta-naphthoflavone, pregnenolone 16 alpha-carbonitrile, and clofibrate have been injected intraperitoneally with chloramphenicol, and inhibition of specific cytochrome P-450 isozymes has been assessed by monitoring the metabolism of warfarin, testosterone, isosafrole, or lauric acid in subsequently prepared hepatic microsomal preparations. Of eight major cytochrome P-450 isozymes which could be monitored in this fashion, three were inhibited by more than 50% by a dose of chloramphenicol of 300 mg/kg, whereas no evidence of inhibition of the remaining isozymes was obtained. P-450PB-C, an isozyme which is present in significant amounts in untreated rats and which is induced approximately 2-fold by phenobarbital, was the most susceptible cytochrome P-450 to inhibition by chloramphenicol both in vivo and in vitro. P-450PB-B, the major phenobarbital-inducible isozyme, and P-450UT-A, a male-specific testosterone 2 alpha- and 16 alpha-hydroxylase, were intermediate in their susceptibility to chloramphenicol. In contrast, the major isozymes induced by beta-naphthoflavone, pregnenolone 16 alpha-carbonitrile, and clofibrate, as well as a constitutive testosterone 7 alpha-hydroxylase, were not inhibited by chloramphenicol.
Mol Pharmacol 1985 Sep
PMID:Isozyme selectivity of the inhibition of rat liver cytochromes P-450 by chloramphenicol in vivo. 403 29

We recently reported that interleukin-3, Steel factor, and erythropoietin all induce the tyrosine phosphorylation of Shc and its association with Grb2 in hemopoietic cell lines. We have now further characterized the proteins that become associated with Shc following stimulation with these cytokines and found that, in response to all three, the tyrosine-phosphorylated form of Shc binds to common 145- and 52-kDa proteins which also become tyrosine phosphorylated in response to these growth factors. The 145-kDa protein, which appears, from antiphosphotyrosine blots of two-dimensional O'Farrell gels, to exist in four different phosphorylation states following cytokine stimulation (with isoelectric points ranging from 7.2 to 7.8), does not appear to be immunologically related to the beta subunit of the interleukin-3 receptor, c-Kit, BCR, ABL, JAK1, JAK2, Sos1, eps15, or insulin receptor substrate 1 protein. Silver-stained sodium dodecyl sulfate gels indicate that the association of the 145-kDa protein with Shc occurs only after cytokine stimulation and that it can bind to the tyrosine-phosphorylated form of Shc in its non-tyrosine-phosphorylated state. The latter finding, in conjunction with the observations that p145 does not bind, in vitro, to the Src homology 2 (SH2) domain of Shc, that it is not present in anti-Grb2 immunoprecipitates, and that a phosphopeptide which blocks the binding of Shc to the SH2 domain of Grb2 also blocks the binding of Shc to p145, suggests that p145 contains an SH2 domain and competes with Grb2 for the same tyrosine-phosphorylated site on Shc. This implicates p145 as a potential regulator of Ras activity and, perhaps, of other as yet unidentified functions of Shc.
Mol Cell Biol 1994 Oct
PMID:Multiple cytokines stimulate the binding of a common 145-kilodalton protein to Shc at the Grb2 recognition site of Shc. 752 59

The carboxyl-terminal 28 amino acids of rabbit cytochrome P450 2C2 are markedly different from those of other rabbit cytochrome P450 2C family members and, substitution of the equivalent amino acids of other cytochrome P450s can confer novel steroid hydroxylase activity to P450 2C2 while the normal lauric acid hydroxylase activity is retained. To determine the basis for the novel steroid hydroxylase activity, amino acids of cytochrome P450 2C1 were substituted for those of cytochrome P450 2C2 and the mutants were expressed in COS-1 cells. There are 13 differences between the sequences of cytochrome P450 2C2 and P450 2C1 in this region, including five nonconservative exchanges of charged and uncharged amino acids. However, only substitution of valine for Ser-473 increased steroid hydroxylase activity to the maximum level expected in a modified cytochrome P450 2C2, which contained additional substitutions in the 368-388 region to maximize progesterone hydroxylase activity. Introduction of this single substitution into cytochrome P450 2C2 resulted in 21-progesterone hydroxylase activity similar to that resulting from substitution of all 28 carboxyl-terminal cytochrome P450 2C1 amino acids. None of the substitutions, with one exception, substantially affected either lauric acid hydroxylase activity or the amount of immunologically reactive cytochrome P450 that was expressed. A glycine substitution for Val-477 reduced activity of both lauric acid hydroxylase and progesterone hydroxylase and altered the regioselectivity of the hydroxylation for both. Homology modeling of cytochrome P450 2C2, based on the cytochrome bacterial P450cam sequence, indicated that the side chains of residue 473 and the other five residues previously shown to affect substrate specificity face the substrate pocket. For four of the six residues, smaller and more hydrophobic residues increased progesterone relative to lauric acid hydroxylation.
Mol Pharmacol 1995 Sep
PMID:Substitution at residue 473 confers progesterone 21-hydroxylase activity to cytochrome P450 2C2. 756 21

BCR-ABL is a deregulated tyrosine kinase expressed in Philadelphia chromosome-positive human leukemias. Prolongation of hematopoietic cell survival by inhibition of apoptosis has been proposed to be an integral component of BCR-ABL-induced chronic myelogenous leukemia. BCR-ABL elicits transformation of both fibroblast and hematopoietic cells and blocks apoptosis following cytokine deprivation in various factor-dependent cells. To elucidate the mechanisms whereby BCR-ABL induces transformation and blocks apoptosis in hematopoietic cells, we examined the biological effects of expression of a series of BCR-ABL mutants. Single amino acid substitutions in the GRB2 binding site (Y177F), Src homology 2 domain (R552L), or an autophosphorylation site in the tyrosine kinase domain (Y793F) do not diminish the antiapoptotic and transforming properties of BCR-ABL in hematopoietic cells, although these mutations were previously shown to drastically reduce the transforming activity of BCR-ABL in fibroblasts. A BCR-ABL molecule containing all three mutations (Y177F/R552L/Y793F) exhibits a severe decrease in transforming and antiapoptotic activities compared with the wild-type BCR-ABL protein in 32D myeloid progenitor cells. Ras is activated, the SHC adapter protein is tyrosine phosphorylated and binds GRB2, and myc mRNA levels are increased following expression of all kinase active BCR-ABL proteins with the exception of the Y177F/R552L/Y793F BCR-ABL mutant in 32D cells. We propose that BCR-ABL uses multiple pathways to activate Ras in hematopoietic cells and that this activation is necessary for the transforming and antiapoptotic activities of BCR-ABL. However, Ras activation is not sufficient for BCR-ABL-mediated transformation. A BCR-ABL deletion mutant (delta 176-427) that activates Ras and blocks apoptosis but has severely impaired transforming ability in 32D cells has been identified. These data suggest that BCR-ABL requires additional signaling components to elicit tumorigenic growth which are distinct from those required to block apoptosis.
Mol Cell Biol 1995 Oct
PMID:Structural and signaling requirements for BCR-ABL-mediated transformation and inhibition of apoptosis. 756 5

Trimethadione(TMO) is regarded as a model drug for estimating the hepatic drug oxidative capacity in vivo. However, the P450 isozymes that are responsible for TMO N-demethylation have not been identified clearly yet. This study was designed to determine these P450 isozymes that participate in the TMO N-demethylation in vivo by employing several typical P450 inhibitors and substrates. Male Sprague-Dawley(SD) rats were pretreated with P450 inhibitors or substrates before TMO(100mg/kg, p.o.) treatment. Serum dimethadione(DMO)/TMO ratios were employed for the assessment of metabolic capacity toward TMO. Pretreatment with imidazole and acetone significantly decreased the DMO/TMO ratios in a dose related manner. Weaker inhibitory effects were observed with SKF525A. However, pretreatment with alpha-naphthoflavone, quinine, debrisoquine, triacetyloleandomycin and lauric acid did not affect the ratios. These results suggest that various forms of P450 are involved in TMO metabolism to some extent and that CYP2E1 is attributed to major P450 isozyme for TMO N-demethylation in vivo.
Res Commun Mol Pathol Pharmacol 1995 Feb
PMID:The effects of inhibitors and substrates of different types of cytochrome P450 isozymes on serum dimethadione/trimethadione ratio in rats in vivo. 774 52

Attempts to solve the fundamental questions regarding the descent of man are dogged by superstitions and unexamined orthodoxies. The origin of humans, established a decade ago based upon cytological analysis of ape chromosomes, continues to be called into question. Although molecular methods have provided a framework for tracing the paths of human evolution, conclusive evidence remains elusive. We have used a single ABL gene probe derived from human chromosome 9 to assess the direction of change in the equivalent ape chromosomes. This approach has resulted in a few surprises which again challenge the prevailing view of early primate evolution based solely on chromosome banding patterns. The ABL proto-oncogene is present on human chromosome 9 at band q34. Similar DNA sequences presumed to represent an ABL gene, are present on chromosome 11 in chimpanzee (Pan troglodytes) but at a different relative location, indicating that the mechanism of the origin of human chromosome 9 is far more complex than has previously been suggested. Nevertheless, in gorilla (Gorilla gorilla) and orangutan (Pongo pygmaeus), the equivalent to human chromosome band 9 q34 is apparently located on chromosome 13 at a putative telomeric position and no discernible differences could be established. Despite the presence of the ABL protooncogene on human equivalent ape chromosomes, molecular systematics will continue to generate enigmas in the evolutionary context until the entire genome is sequenced.
Mol Gen Genet 1994 May 25
PMID:Evolutionary divergence of human chromosome 9 as revealed by the position of the ABL protooncogene in higher primates. 820 81

Two vitellins (Vn-1 and Vn-2) were identified in cockroach ovary. Vn-2 was purified by ion-exchange chromatography using DEAE cellulose and Sepharose CL-6B, and gel filtration using Sephadex G-200 and Sepharose 4B. Vn-2 comprises three subunits with molecular weights of 102, 72 and 40 kDa. Vn-2 contains diacylglycerol and triacylglycerol; their fatty acids are mostly lauric acid and palmitoleic acid. Vn-2 also has phosphatidylcholine and phosphatidylethanolamine but no sphingomyelin. Vn-2 contains large amounts of glutamic acid and aspartic acid but small amounts of tyrosine, phenylalanine, and methionine. Vn-2 gradually decreases during embryonic development; none remains in first instar larvae. It was found that Vn-2 partially reacted immunologically with ovarian extracts of Periplaneta fulginosa but not with those of Blattella germanica. Vn-2 also showed no immunological reaction with extracts from other orders; including Cletus schmidti (Hemiptera), Lucilia illustris (Diptera), Anechura japonica (Dermaptera), Bombyx mori (Lepidoptera), and Ducetia japonica (Orthoptera).
Comp Biochem Physiol Biochem Mol Biol 1994 May
PMID:Purification and characterization of vitellin-2 from the ovary of the American cockroach, Periplaneta americana. 820 88

The c-ABL proto-oncogene is a predominantly nuclear localized tyrosine kinase. A random mutagenesis scheme was used to isolate c-ABL mutants whose expression produced a transformed phenotype in rodent fibroblast cells. An in-frame deletion within the central region of the last exon was identified in one ABL mutant. The mechanism of c-ABL oncogenic activation by mutation within the last exon differs both functionally and structurally from those of v-ABL and BCR/ABL. This class of ABL mutants shows increased tyrosine phosphorylation of cellular proteins in vivo but low levels of autophosphorylation. Last-exon ABL mutants are distinguished from v-ABL or BCR/ABL by their inability to transform primary bone marrow cells or support the growth of transformed pre-B cells. These findings define a new mechanism of oncogenic activation for the ABL kinase through mutations in the last exon which do not require amino-terminal deletions or mutations within the src homology regions.
Mol Cell Biol 1993 Aug
PMID:Oncogenic activation of c-ABL by mutation within its last exon. 833 29

Abelson murine leukemia virus (A-MuLV), a retrovirus that expresses the v-abl oncogene, characteristically induces pre-B-cell lymphomas following in vivo infection of BALB/c mice or in vitro infection of suspensions of fetal liver or bone marrow cells. ABL-MYC, a retrovirus that expresses both v-abl and c-myc, induces solely plasmacytomas in BALB/c mice. To investigate how the addition of overexpression of c-myc to that of v-abl accomplishes this dramatic change in the phenotype of the cells transformed by these closely related retroviruses, we utilized helper-free A-MuLV (psi 2) and ABL-MYC (psi 2) in vitro to infect suspensions of cells from different lymphoid tissues and purified immature and purified mature B cells. As expected, A-MuLV(psi 2) induced only pre-B-cell lymphomas in vivo and in vitro when immature B cells were present. ABL-MYC(psi 2), on the other hand, produced only plasmacytomas, even when purified immature B lymphocytes were infected in vitro. Although the A-MuLV(psi 2)-induced pre-B-cell lymphomas express easily detectable levels of c-myc mRNA, maturation into more-mature forms of B lymphocytes is blocked. The constitutively overexpressed c-myc in the ABL-MYC retrovirus abrogates this block, permits maturation of infected immature B cells, and yields transformed plasma cells.
Mol Cell Biol 1993 Apr
PMID:Addition of constitutive c-myc expression to Abelson murine leukemia virus changes the phenotype of the cells transformed by the virus from pre-B-cell lymphomas to plasmacytomas. 845 30

The BCR gene is implicated in the development of Ph-positive leukemia through its fusion with the nonreceptor tyrosine kinase gene ABL. The normal 160 kDa Bcr protein has several functional domains, and recently one specific role for Bcr was established in the regulation of respiratory burst activity in white blood cells. Bcr expression levels are relatively constant throughout mouse development until adulthood in brain and in hematopoietic tissues, a pattern that is distinctly different from that of the functionally related n-chimerin gene. In the present study, RNA in situ hybridization was used to explore the normal cellular function of Bcr in rodent brain and hematopoietic organs. The data pinpoint the high bcr expression in the brain to the hippocampal pyramidal cell layer and the dentate gyrus, and to the piriform cortex and the olfactory nuclei, reflecting a potentially interesting function for Bcr in these highly specialized brain regions.
Cell Mol Biol Res 1995
PMID:Regional localization and developmental expression of the BCR gene in rodent brain. 858 Oct 68


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