Human papillomavirus E6 and Myc proteins associate in vivo and bind to and cooperatively activate the telomerase reverse transcriptase promoter

AUTOR(ES)

Veldman, Tim

FONTE

National Academy of Sciences

RESUMO

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.

Documentos Relacionados

• Telomerase Activation by Human Papillomavirus Type 16 E6 Protein: Induction of Human Telomerase Reverse Transcriptase Expression through Myc and GC-Rich Sp1 Binding Sites
• Human papillomavirus E6 proteins bind p53 in vivo and abrogate p53-mediated repression of transcription.
• Corrigendum: Human papillomavirus E6 proteins bind p53 in vivo and abrogate p53-mediated repression of transcription
• Sp1 cooperates with c-Myc to activate transcription of the human telomerase reverse transcriptase gene (hTERT)
• Basal and human papillomavirus E6 oncoprotein-induced degradation of Myc proteins by the ubiquitin pathway