Abstract
v-Abl is an oncogenic form of the c-Abl nonreceptor tyrosine kinase. v-Abl induces transcription of c-myc, and c-Myc function is a necessary but not sufficient component of the v-Abl transformation program. Previously we showed that the E2F site in the c-myc promoter is a v-Abl response element and that v-Abl appears to induce c-myc by initiating a phosphorylation cascade that ultimately activates E2F-binding proteins. In this work we have investigated the signaling pathway between the v-Abl tyrosine kinase and activated E2F proteins. We show that the Ras GTPase and Raf1 serine/threonine kinase are required in this pathway. However, in contrast to other aspects of v-Abl signaling, induction of c-myc transcription is independent of the Rac GTPase. Our results also establish a requirement for activated cyclin-dependent kinases (cdks), as v-Abl-dependent induction of c-myc transcription is blocked by cdk inhibitor p21 and induction of c-myc is accompanied by activation of cdk2 and cdk4. Finally, we show that v-Abl-dependent induction of c-myc is accompanied by hyperphosphorylation of pRb, p107, and p130. On the basis of these data, we propose a model for the signaling path from v-Abl to c-myc.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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CDC2-CDC28 Kinases*
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Carrier Proteins*
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinase 4
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Cyclin-Dependent Kinases / genetics
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Cyclin-Dependent Kinases / metabolism*
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DNA-Binding Proteins*
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E2F Transcription Factors
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GTP Phosphohydrolases / genetics
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GTP Phosphohydrolases / metabolism
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Genes, myc*
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Mice
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Oncogene Proteins v-abl / genetics*
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Oncogene Proteins v-abl / metabolism*
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Phosphoprotein Phosphatases / genetics
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Phosphoprotein Phosphatases / metabolism
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Phosphorylation
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-raf
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Retinoblastoma Protein / genetics
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Retinoblastoma Protein / metabolism
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Retinoblastoma-Binding Protein 1
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Signal Transduction
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Transcription Factor DP1
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Transcription Factors / genetics
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Transcription Factors / metabolism
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cdc25 Phosphatases
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ras Proteins / genetics
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ras Proteins / metabolism*
Substances
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Arid4a protein, mouse
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Carrier Proteins
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Cell Cycle Proteins
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DNA-Binding Proteins
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E2F Transcription Factors
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Oncogene Proteins v-abl
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Proto-Oncogene Proteins
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Retinoblastoma Protein
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Retinoblastoma-Binding Protein 1
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Transcription Factor DP1
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Transcription Factors
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-raf
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CDC2-CDC28 Kinases
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Cdk2 protein, mouse
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Cdk4 protein, mouse
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinase 4
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Cyclin-Dependent Kinases
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Phosphoprotein Phosphatases
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cdc25 Phosphatases
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GTP Phosphohydrolases
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ras Proteins