Article

HPV16 E5 protein disrupts the c-Cbl-EGFR interaction and EGFR ubiquitination in human foreskin keratinocytes.

Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202-5120, USA.
Oncogene (Impact Factor: 8.56). 05/2005; 24(15):2585-8. DOI: 10.1038/sj.onc.1208453
Source: PubMed

ABSTRACT The E5 protein of human papillomavirus type 16 (HPV16) is a small hydrophobic protein, which localizes to the cell membrane, Golgi apparatus and endosomes. HPV16 E5 enhances the activation of the epidermal growth factor (EGFR). The activated EGFR is downregulated through the endocytic pathway, where E5 has been shown to inhibit endosomal acidification and trafficking. Ubiquitination of the activated EGFR plays a role in this downregulation. c-Cbl is a ubiquitin ligase that associates with the activated EGFR and targets it for degradation. Since E5 has been shown to form a complex with the EGFR, we tested the hypothesis that E5 affects the interaction of c-Cbl with the EGFR. We found a significant decrease of c-Cbl bound to the EGFR and of ubiquitinated EGFR in the presence of E5. E5 did not affect c-Cbl steady-state level, phosphorylation or translocation to the membrane. This novel result suggests that HPV16 E5 may, at least in part, upregulate EGFR-mediated signal transduction by inhibiting the interaction of c-Cbl with the EGFR, thereby decreasing c-Cbl-mediated degradation of the EGFR.

0 Followers
 · 
82 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Human papillomaviruses (HPVs) are small DNA viruses that are important etiological agents of a spectrum of human skin lesions from benign to malignant. Because of their limited genome coding capacity they express only a small number of proteins, only one of which has enzymatic activity. Additionally, the HPV productive life cycle is intimately tied to the epithelial differentiation program and they must replicate in what are normally non-replicative cells, thus, these viruses must reprogram the cellular environment to achieve viral reproduction. Because of these limitations and needs, the viral proteins have evolved to co-opt cellular processes primarily through protein-protein interactions with critical host proteins. The ubiquitin post-translational modification system and the related ubiquitin-like modifiers constitute a widespread cellular regulatory network that controls the levels and functions of thousands of proteins, making these systems an attractive target for viral manipulation. This review describes the interactions between HPVs and the ubiquitin family of modifiers, both to regulate the viral proteins themselves and to remodel the host cell to facilitate viral survival and reproduction.
    Viruses 09/2014; 6(9):3584-3611. DOI:10.3390/v6093584 · 3.28 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Non-small-cell lung cancer (NSCLC) is one of the most commonly diagnosed malignancies all over the world. The small-molecule tyrosine kinase inhibitors (TKIs) of epidermal growth factor receptor (EGFR) including gefitinib and erlotinib have been used widely for treating NSCLC. Unfortunately, nearly all patients eventually progress by acquired resistance after experiencing marked improvement on these drugs. Because there is no effective therapeutic strategy to treat NSCLC with acquired resistance to EGFR TKIs, we mainly evaluated the effects of luteolin on T790M mutant NSCLC cells. The effect of luteolin on the viability of NSCLC cell and normal cells lines was investigated using the Cell Counting Kit-8 (CCK-8) assay. Luteolin-induced apoptosis was assessed by Bivariate FITC-Annexin V/ PI assay, and Western blot assay was used to test the apoptotic proteins. Co-immunoprecipitation was used to test the luteolin effect between Hsp90 and mutant EGFR. The effect of luteolin on the Akt/mTOR pathway was studied using Western blotting analysis, and the in vivo anti-tumour efficacy was examined in an xenograft model. We found that luteolin exerted remarkable anti-tumorigenic effects on EGFR L858R/T790M mutation and erlotinib-resistant NSCLC both at cell and animal levels. Mechanistically, luteolin induced EGFR degradation through inhibiting the association of Hsp90 and mutant EGFR and therefore obviously prevented PI3K/AKT/mTOR signalling and led to NSCLC cell apoptosis. Our investigation suggests that luteolin may act as a potential candidate for NSCLC therapy especially for treatment to acquired erlotinib-resistant NSCLC patients.
    British Journal of Pharmacology 01/2014; DOI:10.1111/bph.12610 · 4.99 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Human papillomavirus (HPV) infection is clinically very common. It is usually a major risk factor in the development of cutaneous benign lesions, cervical cancer and a variety of other malignancies. The biological function of ubiquitination as an intracellular proteasomal-mediated form of protein degradation and an important modulator in the regulation of many fundamental cellular processes has been increasingly recognized over the last decade. HPV proteins have been demonstrated to evolve different strategies to utilize the ubiquitin system for their own purposes. The putative roles of E3 ubiquitin ligases in HPV-induced carcinogenesis have become increasingly apparent, although the mechanisms remain unclear. In this review we provide an update on the mechanisms of the involvement of E3 ubiquitin ligases in HPV-induced carcinogenesis, focusing on their interaction with HPV proteins and their roles in several signalling pathways. Targeting the E3 ubiquitin ligases might offer potential therapeutic strategies for HPV-related diseases in future.
    The Journal of international medical research 01/2014; 42(2). DOI:10.1177/0300060513506655 · 1.10 Impact Factor

Preview

Download
1 Download
Available from