Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.5.1.18 (glutathione S-transferase)
 22,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We performed cloning and sequence analysis of translocation junctions at 11q- and 22q- (Ph1) chromosomes and the corresponding germline DNAs of a variant Ph1-positive CML with t(9;22;11)(q34;q11;q13). Southern blot analysis using probes for different regions of bcr mapped the translocation break near the 5'-side of bcr exon 4. Cloning, Southern blot analysis and restriction map analysis of both bcr fragments showed that the part of bcr 3'- to the translocation break moved to 11q13. Sequence analysis of the translocation junction on the Ph1 chromosome showed that the translocation break occurred 63 bp upstream of exon 4. Compared to the germline sequence, bcr sequence from the translocated partners showed deletion of seven basepairs at the site of translocation. A probe derived from the 5'-region of the clone isolated from the 11q- chromosome identified clonal rearrangements in the leukemic DNA. Restriction map and sequence analysis showed that this clone consisted of the 3'-half of the glutathione S-transferase Pi (GST-Pi) gene and the 3'-part of bcr. We identified two point mutations in the GST-Pi allele involved in translocation. Northern blot analysis showed that the GST-Pi gene was expressed in the leukemic cells at blast crisis but not at chronic phase; however, no fusion mRNA between GST-Pi and bcr was identified. We did not find any sequence homology between 11q13 DNA and 22q11 DNA around the translocation breakpoints; however, sequences homologous to ALU repeats were identified close to the sites of translocation breaks at 22q11 and 11q13. This study supports our hypothesis that variant Ph1 translocations may occur as primary cytogenetic changes similar to the classical Ph1 translocations.
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PMID:Molecular characterization of a variant Ph1 translocation t(9;22;11) (q34;q11;q13) in chronic myelogenous leukemia (CML) reveals the translocation of the 3'-part of BCR gene to the chromosome band 11q13. 824 27

We have previously reported that the Jak2 tyrosine kinase but not Jak1 is tyrosine phosphorylated in the absence of IL-3 in Bcr-Abl positive M3.16 cells, which are rendered IL-3 independent by BCR-ABL gene expression. We have explored the involvement of Jak2 tyrosine phosphorylation in Bcr-Abl oncogenic effects. Our results indicate that Jak2 became tyrosine-phosphorylated in a number of cell lines expressing Bcr-Abl, when maintained in medium lacking IL-3, whereas Bcr-Abl negative cells lacked Jak2 tyrosine phosphorylation. Jak2 was poorly tyrosine-phosphorylated in cells expressing the SH2 deletion mutant of Bcr-Abl compared to either wild-type Bcr-Abl or its SH3 deletion mutant. Moreover, tyrosine phosphorylation of Jak2 by Bcr-Abl was inhibited by the Abl tyrosine kinase inhibitor, STI 571, in a dose-dependent manner. This inhibition of Bcr-Abl kinase by the drug did not interfere with the ability of Jak2 and Bcr-Abl to form a complex. Studies with deletion mutants of Bcr-Abl indicated that the C-terminal domain of Abl within Bcr-Abl was involved in complex formation with Jak2. Similarly, GST-Abl pull-down assays confirmed the strong binding to Jak2 by the C-terminus of Abl. Jak2 peptide substrate studies indicated that the Bcr-Abl and Abl tyrosine kinases specifically phosphorylated Y1007 of Jak2 but only poorly phosphorylated Y1008. Phosphorylation of Y1007 of Jak2 is known to be critical for its tyrosine kinase activation. Tyrosine residue 1007 of Jak2 was phosphorylated in 32Dp210 cells as measured by Western blotting with a phosphotyrosine 1007 sequence-specific antibody. A kinase-inactive Jak2 mutant blocked the colony forming ability of K562 cells. Tumor formation of K562 cells in nude mice was similarly inhibited by this kinase-inactive Jak2 mutant. This inhibition was independent of Stat5 tyrosine phosphorylation. Furthermore, tyrosine-phosphorylated Jak2 was detected in blood cells from CML patients in blast crisis but not in a normal marrow sample. In summary, these findings provide strong evidence that the Jak2 tyrosine kinase is a critical factor in Bcr-Abl malignant transformation.
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PMID:Involvement of Jak2 tyrosine phosphorylation in Bcr-Abl transformation. 1159 27