A transformation-defective mutant of Abelson murine leukemia virus lacks protein kinase activity.

Witte, Owen N.; Goff, Stephen P.; Rosenberg, Naomi; Baltimore, David

doi:10.1073/pnas.77.8.4993

Cited by 108 publications

(58 citation statements)

References 31 publications

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“…Both are phosphorylated on serine in vivo, but neither protein displays evidence of tyrosine phosphorylation activity in vitro or in vivo (15,20). Because the tyrosine kinase activity of v-abl is mediated by c-abl-derived sequences (31,35), it seems likely that the major structural alteration of c-abl that generated v-abl was an event that unmasked intrinsic kinase activity of c-abl.…”

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confidence: 99%

“…The expression of v-abl kinase activity is correlated with transformation of lymphoid cells in vivo and in vitro (24). In addition, deletion mutagenesis of the A-MuLV genome (21), as well as structural analysis of naturally occurring mutants (35), has revealed that both the transforming activity and the tyrosine kinase activity are encoded in the 45-kilodalton region on the carboxyl side of the gag-abl junction. A subset of this region contains sequences highly homologous to tyrosine kinases encoded by other transforming genes (10,22).…”

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confidence: 99%

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Activation of the c-abl oncogene by viral transduction or chromosomal translocation generates altered c-abl proteins with similar in vitro kinase properties.

Davis¹,

Konopka²,

Witte³

1985

Mol. Cell. Biol.

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153

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The v-abl protein of Abelson murine leukemia virus is a tyrosine-specific kinase. Its normal cellular homolog, murine c-abl, does not possess detectable tyrosine kinase activity in vitro. Previously, we have detected tyrosine kinase activity in vitro for an altered c-abl gene product (c-abl P210) in the K562 human chronic myelogenous leukemia cell line. The expression of this variant c-abl gene product correlates with chromosomal translocation and amplification of the c-abl gene in K562 cells. Like v-abl, c-abl P210 is a fusion protein containing non-abl sequences near the amino terminus of c-abl. We compared the in vitro tyrosine kinase activity of c-abl P210 with that of wild-type murine v-abl. The remarkable similarities of these two proteins with respect to cis-acting autophosphorylation, trans-acting phosphorylation of exogenous substrates, and kinase inhibition, using site-directed abl-specific antisera, suggested that c-abl P210 could function similarly to v-abl in vivo. In addition, c-abl P210 possessed an associated serine kinase activity in immunoprecipitates. The serine kinase activity was not inhibited by site-directed, abl-specific antisera that inhibit the tyrosine kinase activity, suggesting that the serine kinase activity is not an intrinsic property of c-abl P210. Thus, the activation of the c-abl gene in a human leukemia cell line may have functional consequences analogous to activation of the c-abl gene in Abelson murine leukemia virus.

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confidence: 99%

mentioning

confidence: 99%

Activation of the c-abl oncogene by viral transduction or chromosomal translocation generates altered c-abl proteins with similar in vitro kinase properties.

Davis¹,

Konopka²,

Witte³

1985

Mol. Cell. Biol.

Self Cite

153

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show abstract

“…While the catalytic domain is fully contained in the c-abl protein and can be activated in properly designed in vitro assays (31), no in vivo occurrence of tyrosine kinase activity has yet been demonstrated for normal c-abl gene product (30,31,34). On the other hand, the acquisition of constitutive tyrosine kinase activity has been shown to be a requisite for the transforming activity of v-abl oncogene products (35,39,40,52,53). Ph' translocation of the c-abl gene in CML cells then offers a valuable opportunity for comparing, at the gene product level, a spontaneously activated human proto-oncogene with its retrovirus-transduced acutely transforming version.…”

Section: Discussionmentioning

confidence: 99%

Phosphotyrosine antibodies identify the p210c-abl tyrosine kinase and proteins phosphorylated on tyrosine in human chronic myelogenous leukemia cells.

Naldini¹,

Stacchini²,

Cirillo³

et al. 1986

Mol. Cell. Biol.

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Antibodies against phosphotyrosine are a powerful tool with which to identify proteins phosphorylated on tyrosine residues, such as viral oncogene-encoded transforming proteins and their cellular protein substrates. Probed on human leukemia cell lines, phosphotyrosine antibodies recognized a 210,000-molecular-weight protein (p210) in K562 cells, a cell line derived from a Philadelphia (Ph)'-positive chronic myelogenous leukemia (CML), but recognized no protein in control Ph'-negative non-CML leukemia cells. The p210 protein was also recognized by antisera against v-abl-encoded polypeptides and displayed kinase activity, phosphorylating itself on tyrosine, in an immunocomplex kinase assay. These data are consistent with reported findings of the expression of a recombined bcr-abl gene in Ph'-positive CML cells, leading to the synthesis of an altered p210c-abl protein endowed with tyrosine kinase activity. Phosphotyrosine antibodies also detected the expression of the p210c-abl protein in fresh bone marrow cells harvested from CML patients in blast crisis. Besides the p210c-abl protein kinase, phosphotyrosine antibodies recognized other proteins with molecular weights of 110,000, 68,000, and 36,000 (p110, p68, and p36) in K562 cells. When [gamma-32P]ATP was added to nonionic detergent-extracted cells, these proteins became phosphorylated on tyrosine, as confirmed by phosphoamino acid analysis. A comparison with fibroblasts transformed by the v-abl, v-src, and v-fps oncogenes suggested the identity of the p36 protein with the common 36-kilodalton protein substrate of viral oncogene-encoded tyrosine kinases. Enhanced tyrosine phosphorylation of cellular proteins is thus a feature shared by cells transformed by v-abl and cells expressing a rearranged bcr-abl gene.

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“…The normal physiologic function of c-abl is presently unknown although its homologue v-abl is known to have tyrosine kinase activity (4). An abnormally large 8-kb ablrelated RNA transcript has been noted in CML cells (5,6) and this aberrant message appears to be transcribed from the translocated c-abl oncogene on the Ph'.…”

Section: Introductionmentioning

confidence: 99%

Breakpoints on chromosomes 9 and 22 in Philadelphia chromosome-positive chronic myelogenous leukemia (CML). Amplification of rearranged c-abl oncogenes in CML blast crisis.

Collins¹

1986

J. Clin. Invest.

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We surveyed 20 Philadelphia chromosome (Ph') positive chronic myelogenous leukemia (CML) samples by Southern blot hybridization to determine the location ofthe breakpoints that occur on chromosomes 9 and 22 in the Ph' translocation. Only 3 of 20 samples exhibited breakpoints on chromosome 9 within 18 kilobases (kb) of the v-abl homologous sequences. Mapping of these three chromosome 9 breakpoints indicates that each is at a separate location within this 18-kb region, indicating that there are no breakpoint "hot spots" in this area. In contrast, all 20 CML samples exhibited breaks on chromosome 22 within a 5.0-kb Bgl II fragment that lies within the previously described breakpoint cluster region (bcr). Several patients with CML blast crisis exhibiting multiple Ph' chromosomes/metaphase exhibited amplified and rearranged c-abl-related fragments. These additional Ph' chromosomes in blast crisis cells do not arise from a second, independent 9:22 translocation but rather result from a duplication of the preexisting Ph' chromosome.

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A transformation-defective mutant of Abelson murine leukemia virus lacks protein kinase activity.

Cited by 108 publications

References 31 publications

Activation of the c-abl oncogene by viral transduction or chromosomal translocation generates altered c-abl proteins with similar in vitro kinase properties.

Activation of the c-abl oncogene by viral transduction or chromosomal translocation generates altered c-abl proteins with similar in vitro kinase properties.

Phosphotyrosine antibodies identify the p210c-abl tyrosine kinase and proteins phosphorylated on tyrosine in human chronic myelogenous leukemia cells.

Breakpoints on chromosomes 9 and 22 in Philadelphia chromosome-positive chronic myelogenous leukemia (CML). Amplification of rearranged c-abl oncogenes in CML blast crisis.

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