The E7 proteins of low- and high-risk human papillomaviruses share the ability to target the pRB family member p130 for degradation.
High-risk human papillomaviruses (HPVs) (e.g., HPV-16) cause anogenital and head and neck cancers, and low-risk HPVs (e.g., HPV-6) cause benign hyperproliferative disease. The E7 protein of HPV-16 binds all retinoblastoma tumor suppressor protein (pRB) family members with higher affinity than HPV-6E7. The HPV-16 E7 protein has been reported to target pRB family members for degradation and to immortalize cells. Here we tested the hypothesis that the low-risk E7 protein has an intrinsic ability to decrease expression of pRB family members. First, we introduced a high-affinity pRB-binding site into HPV-6 E7 (6E7G22D) and showed that, in human foreskin keratinocytes, HPV-6 E7G22D decreased the level of pRB protein but not pRB mRNA. Second, we analyzed the ability of wild-type HPV-6 E7 to destabilize the other pRB family members, p107 and p130. HPV-6 E7, like HPV-16 E7, decreased the level of p130 protein. This decrease was inhibited by MG132, a proteasome inhibitor. Binding of HPV-6 E7 to p130 was necessary but not sufficient to decrease the level of p130. Furthermore, the destabilization of p130 correlated with a decrease in the expression of involucrin, a differentiation marker. We suggest that the shared activity of HPV-16 E7 and HPV-6 E7 to destabilize p130 and decrease or delay differentiation may be related to the role of E7 in the HPV life cycle. The added ability of HPV-16 E7 to regulate pRB and p107 may be related to oncogenic activity.
Zhang
Benyue
B
Department of Microbiology and Immunology and The Walther Oncology Center, Indiana University School of Medicine and The Walther Cancer Institute, Indianapolis, IN 46202, USA.
Chen
Wei
W
Roman
Ann
A
D000595:Amino Acid Sequence; D001665:Binding Sites; D002454:Cell Differentiation; D002478:Cells, Cultured; D003470:Culture Media; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D008969:Molecular Sequence Data; D009856:Oncogene Proteins, Viral / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D027383:Papillomaviridae / Q000235:genetics / Q000378:metabolism*; D050725:Papillomavirus E7 Proteins; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D050717:Retinoblastoma-Like Protein p130 / Q000378:metabolism*; D012307:Risk Factors
D003470:Culture Media; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D050717:Retinoblastoma-Like Protein p130; C059731:oncogene protein E7, Human papillomavirus type 16; C062495:oncogene protein E7, Human papillomavirus type 6; D046988:Proteasome Endopeptidase Complex