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Degradation of the E7 human papillomavirus oncoprotein by the ubiquitin-proteasome system: targeting via ubiquitination of the N-terminal residue.
- Source :
-
Oncogene [Oncogene] 2000 Nov 30; Vol. 19 (51), pp. 5944-50. - Publication Year :
- 2000
-
Abstract
- The E7 oncoprotein of the high risk human papillomavirus type 16 (HPV-16), which is etiologically associated with uterine cervical cancer, is a potent immortalizing and transforming agent. It probably exerts its oncogenic functions by interacting and altering the normal activity of cell cycle control proteins such as p21WAF1, p27KIP1 and pRb, transcriptional activators such as TBP and AP-1, and metabolic regulators such as M2-pyruvate kinase (M2-PK). Here we show that E7 is a short-lived protein and its degradation both in vitro and in vivo is mediated by the ubiquitin-proteasome pathway. Interestingly, ubiquitin does not attach to any of the two internal Lysine residues of E7. Substitution of these residues with Arg does not affect the ability of the protein to be conjugated and degraded; in contrast, addition of a Myc tag to the N-terminal but not to the C-terminal residue, stabilizes the protein. Also, deletion of the first 11 amino acid residues stabilizes the protein in cells. Taken together, these findings strongly suggest that, like MyoD and the Epstein Barr Virus (EBV) transforming Latent Membrane Protein 1 (LMPI), the first ubiquitin moiety is attached linearly to the free N-terminal residue of E7. Additional ubiquitin moieties are then attached to an internal Lys residue of the previously conjugated molecule. The involvement of E7 in many diverse and apparently unrelated processes requires tight regulation of its function and cellular level, which is controlled in this case by ubiquitin-mediated proteolysis.
- Subjects :
- Adenosine Triphosphate metabolism
Animals
COS Cells
Cell-Free System
Chlorocebus aethiops
HeLa Cells
Humans
Ligases metabolism
Lysine genetics
Lysine metabolism
Mutagenesis, Site-Directed
Papillomavirus E7 Proteins
Protein Structure, Tertiary
Rabbits
Ubiquitins genetics
Multienzyme Complexes metabolism
Oncogene Proteins, Viral metabolism
Ubiquitin-Conjugating Enzymes
Ubiquitins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0950-9232
- Volume :
- 19
- Issue :
- 51
- Database :
- MEDLINE
- Journal :
- Oncogene
- Publication Type :
- Academic Journal
- Accession number :
- 11127826
- Full Text :
- https://doi.org/10.1038/sj.onc.1203989