The alternatively initiated c-Myc proteins differentially regulate transcription through a noncanonical DNA-binding site.
The myc proto-oncogene family has been implicated in multiple cellular processes, including proliferation, differentiation, and apoptosis. The Myc proteins, as heterodimers with Max protein, have been shown to function as activators of transcription through an E-box DNA-binding element, CACGTG. We have now found that the c-Myc proteins regulate transcription through another, noncanonical, DNA sequence. The non-AUG-initiated form of the c-Myc protein, c-Myc 1, strongly and specifically activates transcription of the C/EBP sequences within the EFII enhancer element of the Rous sarcoma virus long terminal repeat. In contrast, comparable amounts of the AUG-initiated form, c-Myc 2, fail to significantly affect enhancer activity. However, both c-Myc proteins trans-activate the CACGTG sequence comparably. In addition, Myc/Max heterodimers, but not Max homodimers, bind to the EFII enhancer sequence in vitro. Finally, c-Myc 1 overexpression, but not c-Myc 2 overexpression, significantly inhibits cell growth. These results reveal new transcriptional activities for the Myc proteins and demonstrate that the different forms of the Myc protein are functionally distinct. These results also suggest an interplay between two different growth regulatory transcription factor families.
Department of Cell Biology, Vanderbilt University, School of Medicine, Nashville, Tennessee 37232-2175.
S R
SR
Hann
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M
Dixit
R C
RC
Sears
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L
Sealy
D000595:Amino Acid Sequence; D000818:Animals; D001358:Avian Sarcoma Viruses / Q000235:genetics; D001483:Base Sequence; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D050976:Basic-Leucine Zipper Transcription Factors; D001665:Binding Sites; D002455:Cell Division / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010442:Peptide Chain Initiation, Translational; D014176:Protein Biosynthesis; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D012091:Repetitive Sequences, Nucleic Acid; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D050976:Basic-Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; C000715470:MAS1 protein, human; C499330:MAX protein, human; C067850:Myc associated factor X; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors; C068422:Max protein, mouse; D004247:DNA