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1.
Int J Cancer ; 125(9): 2014-20, 2009 Nov 01.
Article in English | MEDLINE | ID: mdl-19551855

ABSTRACT

Human papillomavirus (HPV)-induced carcinogenesis is critically dependent on the activities of the viral E6 and E7 oncogenes. Here, we demonstrate that expression of the putative tumor suppressor gene B-cell translocation gene-2 (BTG2) is reinduced in HPV16- and HPV18-positive cancer cells on silencing of viral oncogene expression, indicating that BTG2 is repressed by oncogenic HPVs. Inhibition of BTG2 expression was mediated by the HPV E6 oncogene and occurred in a p53-dependent manner. Luciferase reporter gene analyses revealed that BTG2 repression takes place at the transcriptional level and is dependent on the integrity of the major p53-response element within the BTG2 promoter. Ectopic expression of BTG2 acted antiproliferative in cervical cancer cells. Tissue specimens commonly exhibited reduced BTG2 protein levels in HPV-positive high-grade lesions (CIN2/3) and cervical carcinomas, when compared with normal cervical epithelium. These findings identify the antiproliferative BTG2 gene as a novel cellular target blocked by the HPV E6 oncoprotein.


Subject(s)
Genes, Tumor Suppressor , Human papillomavirus 16/genetics , Human papillomavirus 18/genetics , Immediate-Early Proteins/genetics , Cell Proliferation , DNA-Binding Proteins/genetics , HeLa Cells , Human papillomavirus 16/pathogenicity , Human papillomavirus 18/pathogenicity , Humans , Oncogene Proteins, Viral/genetics , Repressor Proteins/genetics , Tumor Suppressor Protein p53/physiology , Tumor Suppressor Proteins
2.
J Mol Med (Berl) ; 87(3): 321-31, 2009 Mar.
Article in English | MEDLINE | ID: mdl-19099279

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.


Subject(s)
Oncogene Proteins, Viral/metabolism , Peptides/metabolism , Repressor Proteins/metabolism , 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 , Peptide Library , Peptides/genetics , Protein Binding , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/metabolism , Repressor Proteins/genetics , Transfection , Tumor Suppressor Protein p53/metabolism , Two-Hybrid System Techniques , Ubiquitination
3.
J Mol Med (Berl) ; 85(11): 1253-62, 2007 Nov.
Article in English | MEDLINE | ID: mdl-17589817

ABSTRACT

Specific types of human papillomaviruses (HPVs) cause cervical cancer, the second most common tumor in women worldwide. Both cellular transformation and the maintenance of the oncogenic phenotype of HPV-positive tumor cells are linked to the expression of the viral E6 and E7 oncogenes. To identify downstream cellular target genes for the viral oncogenes, we silenced endogenous E6 and E7 expression in HPV-positive HeLa cells by RNA interference (RNAi). Subsequently, we assessed changes of the cellular transcriptome by genome-wide microarray analysis. We identified 648 genes, which were either downregulated (360 genes) or upregulated (288 genes), upon inhibition of E6/E7 expression. A large fraction of these genes is involved in tumor-relevant processes, such as apoptosis control, cell cycle regulation, or spindle formation. Others may represent novel cellular targets for the HPV oncogenes, such as a large group of C-MYC-associated genes involved in RNA processing and splicing. Comparison with published microarray data revealed a substantial concordance between the genes repressed by RNAi-mediated E6/E7 silencing in HeLa cells and genes reported to be upregulated in HPV-positive cervical cancer biopsies.


Subject(s)
DNA-Binding Proteins/genetics , Gene Expression Profiling , Gene Expression Regulation, Viral , Human papillomavirus 18/genetics , Oncogene Proteins, Viral/genetics , RNA Interference , Cell Cycle/drug effects , Cluster Analysis , Female , Gene Expression Regulation, Viral/drug effects , Gene Regulatory Networks , HeLa Cells , Humans , RNA Processing, Post-Transcriptional/drug effects , RNA, Small Interfering/pharmacology , Repressor Proteins/metabolism , Uterine Cervical Neoplasms/genetics , Uterine Cervical Neoplasms/virology
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