E6 protein

Nguyen ML, Nguyen MM, Lee D, Griep AE, Lambert PF (2003) The PDZ ligand domain of the human papiUomavims type 16 E6 protein is required for E6 s induction of epithehal hyperplasia in vivo. J Virol 77 6957-6964... 

Mailer That is a question I have been wanting to address. The apoptosis response can be driven wholly by a maternal programme that doesn t require transcription. If it is p53-dependent, it would be a non-transcriptional effect of p53. We haven t been able to completely get rid of p53. The most direct approach we have tried is to inject the papilloma virus E6 protein into embryos. This is an E3 ubiquitin ligase that degrades p53. There is something like lOng of p53 in every oocyte, so we can only get rid of half of this. Thus we haven t been able to answer the question of whether this response is p53 dependent or not. 

Fig. 2.17. Degradation of the tumor suppressor protein p53 by the ubiquitin-proteosome system. The oncoprotein E6 of the human papilloma virus (HPV) forms a specific complex with the p53 protein and can thus induce the degradation of p53. The E6-p53 complex is recognized by E6-AP, a E3 enzyme of the ubiquitin pathway, as a target protein, whereby a ubiquitin residue is transferred to a lysine residue of p53. In this process, the E6 protein serves as the recognition element for ubiquitin hgation of p53.

Fig. 2.11 Ubiquitinylation of the tumor suppressor protein p53. The attachment of ubiquitin molecules to p53 is catalyzed by the Hect-domain E3 ubiquitin ligase E6-AP which receives the activated ubiquitin from an E2 enzyme. An intermediate is formed where the ubiquitin is linked via a thioester bond to an active site cysteine of E6-AP. The E6 protein binds both to E6-AP and p53 and confers substrate specificity. C. cysteine K lysine.

Another manifestation of genetic instability is an abnormal number of centro-somes. Centrosomes can be stained and quantified in an assay using anti-centrin antibodies. Both, genetic instability and loss of genomic integrity, are often posttransformation events. However, under certain circumstances they can contribute to cellular transformation directly. An example is the transformation by the human papillomavirus (HPV) E7 protein. The HPV E7 and E6 proteins are the two HPV oncogenes found in 99.3% of all cervical cancers. 

Lechner, M.S., Mack, D.H., Finicle, A.B., Crook, T., Vous-den, K.H. and Laimins, L.A. (1992) Human papillomavirus E6 proteins bind p53 in vivo and abrogate p53-mediated repression of transcription. EMBO T. 11 3045-3052. 

Filippova M, Song H. Connolly JL et al. Ihe human papillomavirus 16 E6 protein binds to tumor necrosis factor (TNF) R1 and protects cells from TNF-induced apoptosis. J Biol Chem 2002 277(24) 21730-21739. 

Furthermore, as HPV 18-E6 protein may be one of the crucial proteins for cervical carcinoma cells, the antisense effect might be attributed to the effective suppression of the protein synthesis. The detailed clarification of such inhibitory effects is now under investigation. 

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