Oncogenic human papillomaviruses block expression of the B-cell translocation gene-2 tumor suppressor gene.
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.
Cullmann
Claire
C
Molecular Therapy of Virus-Associated Cancers, German Cancer Research Center, Heidelberg, Germany.
Hoppe-Seyler
Karin
K
Dymalla
Susanne
S
Lohrey
Claudia
C
Scheffner
Martin
M
Dürst
Matthias
M
Hoppe-Seyler
Felix
F
D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000235:genetics; D016147:Genes, Tumor Suppressor; D006367:HeLa Cells; D052162:Human papillomavirus 16 / Q000235:genetics* / Q000472:pathogenicity; D052161:Human papillomavirus 18 / Q000235:genetics* / Q000472:pathogenicity; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics*; D009856:Oncogene Proteins, Viral / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D025521:Tumor Suppressor Proteins
D004268:DNA-Binding Proteins; C068651:E6 protein, Human papillomavirus type 16; C052603:E6 protein, Human papillomavirus type 18; D017874:Immediate-Early Proteins; D009856:Oncogene Proteins, Viral; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C070114:BTG2 protein, human