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

Susanne Dymalla; Martin Scheffner; Elvira Weber; Peter Sehr; Claudia Lohrey; Felix Hoppe-Seyler; Karin Hoppe-Seyler

doi:10.1007/s00109-008-0432-1

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.

Authors

Susanne Dymalla¹, Martin Scheffner, Elvira Weber, Peter Sehr, Claudia Lohrey, Felix Hoppe-Seyler, Karin Hoppe-Seyler

Affiliation

¹ German Cancer Research Center, Im Neuenheimer Feld, Heidelberg, Germany.

PMID: 19099279
DOI: 10.1007/s00109-008-0432-1

Abstract

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

Substances

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