A novel peptide motif binding to and blocking the intracellular activity of the human papillomavirus E6 oncoprotein

J Mol Med (Berl). 2009 Mar;87(3):321-31. doi: 10.1007/s00109-008-0432-1. Epub 2008 Dec 21.


Specific types of human papillomaviruses (HPVs) cause cervical cancer. The viral E6 oncogene is a critical factor for maintaining the malignant phenotype of HPV-positive tumour cells. By yeast two-hybrid screening of a randomised peptide expression library, we isolated linear short peptides, which specifically bind to the HPV16 E6 oncoprotein. Sequence alignments and mutational analyses of the peptides identified a hitherto undiscovered E6-binding motif. Intracellular expression of a peptide containing the novel E6-binding motif resulted in inhibition of colony formation capacity, specifically of HPV16-positive cancer cells. A solubility-optimised variant of the peptide was created, which binds to HPV16 E6 with high affinity. Its intracellular expression efficiently induced apoptosis in HPV16-positive cancer cells. This was linked to restoration of intracellular p53 activities. Thus, this newly identified E6-binding motif could form a novel basis for the development of rational strategies for the treatment of HPV16-positive preneoplastic and neoplastic lesions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Amino Acid Sequence
  • Binding Sites / genetics
  • Blotting, Western
  • Cell Line, Tumor
  • Cell Proliferation
  • Discs Large Homolog 1 Protein
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • HeLa Cells
  • Humans
  • In Situ Nick-End Labeling
  • Kinetics
  • Membrane Proteins / metabolism
  • Molecular Sequence Data
  • Oncogene Proteins, Viral / genetics
  • Oncogene Proteins, Viral / metabolism*
  • Peptide Library
  • Peptides / genetics
  • Peptides / metabolism*
  • Protein Binding
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Transfection
  • Tumor Suppressor Protein p53 / metabolism
  • Two-Hybrid System Techniques
  • Ubiquitination


  • Adaptor Proteins, Signal Transducing
  • DLG1 protein, human
  • Discs Large Homolog 1 Protein
  • E6 protein, Human papillomavirus type 16
  • Membrane Proteins
  • Oncogene Proteins, Viral
  • Peptide Library
  • Peptides
  • Recombinant Fusion Proteins
  • Repressor Proteins
  • Tumor Suppressor Protein p53
  • Green Fluorescent Proteins