v-Abl activates c-myc transcription through the E2F site.
The v-abl oncogene of Abelson murine leukemia virus encodes a deregulated form of the cellular nonreceptor tyrosine kinase. v-Abl activates c-myc transcription, and c-Myc is an essential downstream component in the v-Abl transformation program. To explore the mechanism by which v-Abl activates c-myc transcription, a cotransfection assay was developed. We show that transactivation of a c-myc promoter by v-Abl requires the SH1 (tyrosine kinase) and SH2 domains of v-Abl; the C-terminal domains are not required for transactivation. The assay also identified the E2F site in the c-myc promoter as a v-Abl-responsive element. In addition, multimerized E2F sites were shown to be sufficient to confer v-Abl-dependent activation on a minimal promoter. This is the first identification of a v-Abl response element for transcriptional activation. v-Abl tyrosine kinase-dependent changes in proteins binding the c-myc E2F site were also demonstrated, including induction of a complex containing DP1, p107, cyclin A, and cdk2. Identification of v-Abl-dependent changes in E2F-binding proteins provides an important link between v-Abl, transcription, cell cycle regulation, and control of cellular growth.
Integrated Program in Cellular, Molecular and Biophysical Studies, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
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Wong
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Zou
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Merrell
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Patel
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Marcu
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Chellappan
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Calame
D000011:Abelson murine leukemia virus / Q000235:genetics; D000818:Animals; D001402:B-Lymphocytes; D001483:Base Sequence; D001665:Binding Sites; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D002460:Cell Line; D017931:DNA Primers; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D005347:Fibroblasts / Q000378:metabolism; D005434:Flow Cytometry; D016313:Genes, abl; D016259:Genes, myc; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D016374:Oncogene Proteins v-abl / Q000378:metabolism*; D010957:Plasmids; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis* / Q000235:genetics; D011994:Recombinant Proteins / Q000096:biosynthesis; D056465:Retinoblastoma-Binding Protein 1; D017384:Sequence Deletion; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D017931:DNA Primers; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D016374:Oncogene Proteins v-abl; D016271:Proto-Oncogene Proteins c-myc; D011994:Recombinant Proteins; D056465:Retinoblastoma-Binding Protein 1; D014157:Transcription Factors