Human papillomavirus E6 and Myc proteins associate in vivo and bind to and cooperatively activate the telomerase reverse transcriptase promoter.
The papillomavirus E6 protein binds and directs the ubiquitin-dependent degradation of the p53 tumor suppressor protein. Independent of this p53-degradative function, however, E6 induces cellular telomerase activity. This increase in enzyme activity reflects E6-enhanced transcription of the human telomerase reverse transcriptase (hTERT) catalytic subunit, but the molecular basis for this ... transactivation is unknown. In the present study, we demonstrate that E6/Myc interactions regulate hTERT gene expression. Mad protein, a specific antagonist of Myc, repressed E6-mediated transactivation of the hTERT promoter and this repression was relieved by Myc overexpression. The proximal Myc/ Max-binding element (E-box) in the hTERT promoter was the major determinant of both E6 and Myc responsiveness in keratinocytes. E6 did not alter Myc protein expression or Myc/Max association, and the induction of hTERT by Myc/E6 was independent of Myc phosphorylation at Thr-58/Ser-62 within the transactivation domain. However, immunoprecipitation studies demonstrated that endogenous Myc protein coprecipitated with E6 protein and chromatin immunoprecipitation analyses demonstrated that both E6 and Myc proteins bound to a minimal 295-bp hTERT promoter. Only the "high-risk" E6 proteins bound to the hTERT promoter, consistent with their preferential ability to induce telomerase. The observation that E6 associates with Myc complexes and activates a Myc-responsive gene identifies a mechanism by which this oncogene can modulate cell proliferation and differentiation.
Mesh Terms:
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Basic-Leucine Zipper Transcription Factors, Binding Sites, Cells, Cultured, DNA, DNA-Binding Proteins, Enzyme Induction, Genes, myc, Hela Cells, Humans, Keratinocytes, Oncogene Proteins, Viral, Papillomaviridae, Papillomavirus E7 Proteins, Precipitin Tests, Promoter Regions, Genetic, Protein Binding, Protein Interaction Mapping, Proto-Oncogene Proteins c-myc, Recombinant Fusion Proteins, Regulatory Sequences, Nucleic Acid, Repressor Proteins, Telomerase, Transcription Factors, Transcriptional Activation, Tumor Cells, Cultured
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Basic-Leucine Zipper Transcription Factors, Binding Sites, Cells, Cultured, DNA, DNA-Binding Proteins, Enzyme Induction, Genes, myc, Hela Cells, Humans, Keratinocytes, Oncogene Proteins, Viral, Papillomaviridae, Papillomavirus E7 Proteins, Precipitin Tests, Promoter Regions, Genetic, Protein Binding, Protein Interaction Mapping, Proto-Oncogene Proteins c-myc, Recombinant Fusion Proteins, Regulatory Sequences, Nucleic Acid, Repressor Proteins, Telomerase, Transcription Factors, Transcriptional Activation, Tumor Cells, Cultured
Proc. Natl. Acad. Sci. U.S.A.
Date: Jul. 08, 2003
PubMed ID: 12821782
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