Induction of c-myc transcription by the v-Abl tyrosine kinase requires Ras, Raf1, and cyclin-dependent kinases.
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.
Zou
X
X
Department of Biochemistry, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
Rudchenko
S
S
Wong
K
K
Calame
K
K
D000818:Animals; D042846:CDC2-CDC28 Kinases; D002352:Carrier Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism; D016259:Genes, myc; D051379:Mice; D016374:Oncogene Proteins v-abl / Q000235:genetics* / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D019908:Proto-Oncogene Proteins c-raf; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism; D056465:Retinoblastoma-Binding Protein 1; D015398:Signal Transduction; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D020687:cdc25 Phosphatases; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
C533431:Arid4a protein, mouse; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D016374:Oncogene Proteins v-abl; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein; D056465:Retinoblastoma-Binding Protein 1; D050680:Transcription Factor DP1; D014157:Transcription Factors; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D042846:CDC2-CDC28 Kinases; C495893:Cdk2 protein, mouse; C495902:Cdk4 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases; D010749:Phosphoprotein Phosphatases; D020687:cdc25 Phosphatases; D020558:GTP Phosphohydrolases; D018631:ras Proteins