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)

SH2 (src homology region 2) domains are implicated in protein-protein interactions involved in signal transduction pathways. Isolated SH2 domains bind proteins that are tyrosine phosphorylated. A novel, phosphotyrosine-independent binding interaction between BCR, the Philadelphia chromosome breakpoint cluster region gene product, and the SH2 domain of its translocation partner c-ABL has recently been reported. We have examined the ability of additional SH2 domains to bind phosphotyrosine-free BCR and compared this with their ability to bind tyrosine-phosphorylated c-ABL 1b. Of 11 individual SH2 domains examined, 8 exhibited relatively high affinity for c-ABL 1b, whereas only 4 exhibited relatively high affinity for BCR. Binding of tyrosine-phosphorylated c-ABL 1b by the relatively high-affinity ABL and ARG SH2 domains was quantitatively analyzed, and equilibrium dissociation constants for both interactions were estimated to be in the range of 5 x 10(-7) M. The ABL SH2 domain exhibited relatively high affinity for phosphotyrosine-free BCR as well; however, this interaction appears to be about two orders of magnitude weaker than binding of tyrosine-phosphorylated c-ABL 1b. The ARG SH2 domain exhibited relatively weak affinity for BCR and was determined to bind about 10-fold less strongly than the ABL SH2 domain. The ABL and ARG SH2 domains differ by only 10 of 91 amino acids, and the substitution of ABL-specific amino acids into either the amino- or carboxy-terminal half of the ARG SH2 domain was found to increase its affinity for BCR. We discuss these results in terms of a model which has been proposed for peptide binding by class I histocompatibility glycoproteins.
Mol Cell Biol 1992 Nov
PMID:A limited set of SH2 domains binds BCR through a high-affinity phosphotyrosine-independent interaction. 138 90

Microsomes prepared from COS-1 cells transiently expressing rabbit cytochromes P450 2C1 and 2C2 catalyzed the metabolism of arachidonic acid to predominantly 11,12- and 14,15-epoxyeicosatrienoic acids (EETs) when microsomal epoxide hydrolase activity was inhibited by 0.2 mM 1,2-epoxy-3,3,3-trichloropropane. P450 2C2 catalyzed the formation of 11,12-EET and 14,15-EET at a ratio of 3.0 and also produced 19-hydroxyeicosatetraenoic acid (19-HETE). The 11,12-EET, 14,15-EET, and 19-HETE represented 48.3, 15.9, and 12.8%, respectively, of the total metabolites formed. P450 2C1 produced a similar but distinct ratio of 11,12-EET to 14,15-EET (2.0) and did not produce any detectable 19-HETE. The 11,12-EET and 14,15-EET represented 63.0 and 31.1%, respectively, of the total metabolites formed. The 8,9- and 5,6-EETs were not detected with either enzyme. The ratio of the 11,12-EET to 14,15-EET was 1.5 with P450 2CAA, a P450 arachidonic acid epoxygenase (P450 2CAA) that had an amino-terminal sequence identical to that of P450 2C2 [J. Biol. Chem. 267:5552-5559 (1992)]. P450 2C1, 2C2, and 2CAA metabolized lauric acid. The ratio of omega-1- to omega-hydroxylated laurate was 3.6, 3.4, and 2.4 for P450 2CAA, P450 2C2, and P450 2C1, respectively. Purified P450 2CAA had a slightly greater apparent molecular weight than expressed P450 2C2 on sodium dodecyl sulfate-polyacrylamide gels. The results clearly establish that rabbit P450 2C1 and 2C2 are arachidonic acid epoxygenases, and they suggest that P450 2CAA and 2C2 are very similar but may not be identical isoforms.
Mol Pharmacol 1992 Dec
PMID:Identification of rabbit cytochromes P450 2C1 and 2C2 as arachidonic acid epoxygenases. 148 Jan 36

Two forms of activated BCR/ABL proteins, P210 and P185, that differ in BCR-derived sequences, are associated with Philadelphia chromosome-positive leukemias. One of these diseases is chronic myelogenous leukemia, an indolent disease arising in hematopoietic stem cells that is almost always associated with the P210 form of BCR/ABL. Acute lymphocytic leukemia, a more aggressive malignancy, can be associated with both forms of BCR/ABL. While it is virtually certain that BCR/ABL plays a central role in both of these diseases, the features that determine the association of a particular form with a given disease have not been elucidated. We have used the bone marrow reconstitution leukemogenesis model to test the hypothesis that BCR sequences influence the ability of activated ABL to transform different types of hematopoietic cells. Our studies reveal that both P185 and P210 induce a similar spectrum of hematological diseases, including granulocytic, myelomonocytic, and lymphocytic leukemias. Despite the similarity of the disease patterns, animals given P185-infected marrow developed a more aggressive disease after a shorter latent period than those given P210-infected marrow. These data demonstrate that the structure of the BCR/ABL oncoprotein does not affect the type of disease induced by each form of the oncogene but does control the potency of the oncogenic signal.
Mol Cell Biol 1991 Sep
PMID:Differences in oncogenic potency but not target cell specificity distinguish the two forms of the BCR/ABL oncogene. 187 48

The t(9;22) Philadelphia chromosome translocation fuses 5' regulatory and coding sequences of the BCR gene to the c-ABL proto-oncogene. This results in the formation of hybrid BCR-ABL mRNAs and proteins. The shift in ABL transcriptional control to the BCR promoter may play a role in cellular transformation mediated by this rearrangement. We have functionally localized the BCR promoter to a region 1 kb 5' of BCR exon 1 coding sequences by using a chloramphenicol acetyltransferase reporter gene assay. Nucleotide sequence analysis of this region revealed many consensus binding sequences for transcription factor SP1 as well as two potential CCAAT box binding factor sites and one putative helix-loop-helix transcription factor binding site. No TATA-like or "initiator" element sequences were found. Because of low steady-state levels of BCR mRNA and the high GC content (78%) of the promoter region, definitive mapping of transcription start sites required artificial amplification of BCR promoter-directed transcripts. Overexpression from the BCR promoter in a COS cell system was effective in demonstrating multiple transcription initiation sites. In order to assess the effects of chromosomal translocation on the transcriptional control of the BCR gene, we determined S1 nuclease protection patterns of poly(A)+ RNA from tumor cell lines. No differences were observed in the locations and levels of BCR transcription initiation sites between those lines that harbored the t(9;22) translocation and those that did not. This demonstrates that BCR promoter function remains intact in spite of genomic rearrangement. The BCR promoter is structurally similar to the ABL promoters. Together, this suggests that the structural fusion of BCR-ABL and not its transcriptional deregulation is primarily responsible for the transforming effect of the t(9;22) translocation.
Mol Cell Biol 1991 Apr
PMID:Characterization of the BCR promoter in Philadelphia chromosome-positive and -negative cell lines. 190 Sep 18

Interleukin-7 (IL-7) is a potent stimulator of pre-B-lymphocyte proliferation. Pre-B cells transformed by a variety of oncogenes including those of the ABL protein tyrosine kinase family were screened for endogenous IL-7 mRNA expression by polymerase chain reaction and a sensitive bioassay for secreted IL-7. Some v-abl but none of the BCR/ABL, v-src, v-fms, v-myc, v-ras, or v-raf transformants analyzed contained elevated IL-7 transcripts. None of the cell lines secreted detectable bioactivity. We overexpressed IL-7 via a retroviral vector in an IL-7-dependent pre-B cell line to assess the potential for autocrine growth stimulation and malignant transformation. We achieved dramatic deregulation of IL-7 translational suppression by removing portions of the 5' flanking region. Levels of IL-7 expression much greater than those needed to establish factor-independent growth did not induce colony formation in agar by IL-7-expressing pre-B cell lines, and the majority of these lines were nontumorigenic in syngeneic mice. The same pre-B cell line transformed by v-abl displayed a highly malignant phenotype while containing dramatically lower IL-7 transcript levels. We conclude that endogenous IL-7 expression is not a necessary event in transformation of pre-B cells, nor is it sufficient to explain the malignant phenotype in v-abl-transformed cells. Up regulation of endogenous IL-7 expression in some transformed pre-B cells may be one of several synergistic events which can lead to malignant conversion.
Mol Cell Biol 1991 Feb
PMID:Hyperexpression of interleukin-7 is not necessary or sufficient for transformation of a pre-B lymphoid cell line. 199 Feb 88

The c-abl proto-oncogene encodes a cytoplasmic tyrosine kinase which is homologous to the src gene product in its kinase domain and in the upstream kinase regulatory domains SH2 (src homology region 2) and SH3 (src homology region 3). The murine v-abl oncogene product has lost the SH3 domain as a consequence of N-terminal fusion of gag sequences. Deletion of the SH3 domain is sufficient to render the murine c-abl proto-oncogene product transforming when myristylated N-terminal membrane localization sequences are also present. In contrast, the human BCR/ABL oncogene of the Philadelphia chromosome translocation has an intact SH3 domain and its product is not myristylated at the N terminus. To analyze the contribution of BCR-encoded sequences to BCR/ABL-mediated transformation, the effects of a series of deletions and substitutions were assessed in fibroblast and hematopoietic-cell transformation assays. BCR first-exon sequences specifically potentiate transformation and tyrosine kinase activation when they are fused to the second exon of otherwise intact c-ABL. This suggests that BCR-encoded sequences specifically interfere with negative regulation of the ABL-encoded tyrosine kinase, which would represent a novel mechanism for the activation of nonreceptor tyrosine kinase-encoding proto-oncogenes.
Mol Cell Biol 1991 Apr
PMID:BCR first exon sequences specifically activate the BCR/ABL tyrosine kinase oncogene of Philadelphia chromosome-positive human leukemias. 200 81

The tyrosine kinase P210 is the gene product of the rearranged BCR-ABL locus on the Philadelphia chromosome (Ph1), which is found in leukemic cells of patients with chronic myelogenous leukemia. It has a weakly oncogenic effect in immature murine hematopoietic cells and does not transform NIH 3T3 cells. We have found that P210 has a strikingly different effect in Rat-1 cells, another line of established rodent fibroblasts. Stable expression of P210 in Rat-1 cells caused a distinct morphological change and conferred both tumorigenicity and capacity for anchorage-independent growth. The introduction of v-myc into Rat-1 cells expressing P210 led to complete morphological transformation and enhanced tumorigenicity. No such interaction took place in NIH 3T3 cells. Thus, Rat-1 cells can be used to detect cooperation between BCR-ABL and other oncogenes and may prove useful for the identification of secondary oncogenic events in chronic myelogenous leukemia.
Mol Cell Biol 1989 Mar
PMID:The BCR-ABL oncogene transforms Rat-1 cells and cooperates with v-myc. 272 97

The Philadelphia chromosome (t9:22;q34:q11) is found in more than 90% of patients with chronic myelogenous leukemia, in 10 to 20% of patients with acute lymphocytic leukemia, and in 1 to 2% of patients with acute myelogenous leukemia. Alternative chimeric oncogenes are formed by splicing different sets of BCR gene exons on chromosome 22 across the translocation breakpoint to a common set of ABL oncogene sequences on chromosome 9. This results in an 8.7-kilobase mRNA that encodes the P210 BCR-ABL gene product commonly found in patients with chronic myelogenous leukemia or a 7.0-kilobase mRNA that produces the P185 BCR-ABL gene product found in most Philadelphia chromosome-positive patients with acute lymphocytic leukemia. To compare the efficiency of growth stimulation by these two proteins, we derived cDNA clones for each with identical 5' and 3' untranslated regions and expressed them from retrovirus vectors. Matched stocks were compared for potency to transform immature B-lymphoid lineage precursors. The growth-stimulating effects of P185 for this cell type were found to be significantly greater than those of P210. Structural changes in BCR may regulate the effectiveness of the ABL tyrosine kinase function, as monitored by lymphocyte growth response. Changes in mitogenic potency may help to explain the more acute leukemic presentation usually associated with expression of the P185 BCR-ABL oncogene.
Mol Cell Biol 1989 May
PMID:Alternative forms of the BCR-ABL oncogene have quantitatively different potencies for stimulation of immature lymphoid cells. 274 38

The BCR/ABL gene, formed by the Philadelphia chromosome translocation (Ph1) of human chronic myelogenous leukemia, encodes an altered ABL gene product, P210. P210 is strongly implicated in the malignant process of chronic myelogenous leukemia, but it precise role is unknown. Infection of long-term bone marrow cultures enriched for B-lymphoid cell types with a Moloney murine leukemia virus retroviral vector containing the BCR/ABL cDNA resulted in clonal outgrowths of immature B-lymphoid cells which expressed abundant P210 kinase activity. Surprisingly, infection of long-term myeloid lineage-enriched cultures also resulted in clonal outgrowths of immature B-lymphoid cells. The P210-expressing lymphoid cell lines resulting from either type of culture were resistant to the lethal effects of corticosteroids. These findings indicate that high levels of P210 expressed from a Moloney murine leukemia virus long terminal repeat preferentially stimulate the growth of immature B-lineage cells, and this effect is apparent even in myeloid lineage-enriched cultures, in which few if any lymphoid cells can be detected prior to infection.
Mol Cell Biol 1988 Oct
PMID:Selective transformation of primitive lymphoid cells by the BCR/ABL oncogene expressed in long-term lymphoid or myeloid cultures. 326 66

In the present study we have investigated the influence of sex on the specificity of mouse renal microsomes toward endogenous and xenobiotic substrates. Renal microsomes from C3H/HeJ mice were characterized by the following: a 4- to 5-fold male predominance in cytochrome P-450 concentration; a difference between male and female renal microsomes in the absorption maximum for the reduced P-450 . CO complex, 450 and 452 nm, respectively; a lack of a sex difference in lauric acid 12-hydroxylase activity; an 18-fold sex difference (M greater than F) in progesterone 16 alpha-hydroxylase activity; and 8- to 10-fold sex differences (M greater than F) in progesterone 15 alpha-hydroxylase, dimethylnitrosamine demethylase, and lauric acid 11-hydroxylase activities. Treatment of female mice with testosterone propionate selectively induced lauric acid 11-hydroxylase and dimethylnitrosamine demethylase activities 8- and 14-fold, respectively, but had no effect on progesterone 15 alpha- and 16 alpha-hydroxylase activities or on the high female rate of lauric acid 12-hydroxylation. Inhibition studies conducted with male mouse renal microsomes revealed that of the substrates examined, only testosterone inhibited the 15 alpha- and 16 alpha-hydroxylations of progesterone in vitro. In addition, progesterone 15 alpha-hydroxylase was distinguished from 16 alpha-hydroxylase by the greater degree of testosterone inhibition (68 and 44%, respectively) and by sensitivity to metyrapone inhibition. Mouse renal cytochrome P-450 heterogeneity is indicated by the selective effects of androgen induction and metyrapone inhibition. Moreover, distinct modes of regulation are observed between the isozymes involved in steroid hydroxylation and those which catalyze the 11- and 12-hydroxylations of lauric acid in mouse renal microsomes.
Mol Pharmacol 1985 Sep
PMID:Major differences in the specificity and regulation of mouse renal cytochrome P-450-dependent monooxygenases. A comparison of xenobiotic and endogenous substrates. 387 82


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