Regulation of the human papillomavirus oncoproteins by differential phosphorylation.
Human papillomaviruses (HPVs) are intimately associated with the development of cervical cancer. The virus encodes two oncoproteins, E6 and E7, that are primarily responsible for inducing malignant transformation. The last few years have seen significant progress in elucidating the mechanisms by which these two viral proteins bring about cell transformation. Both proteins interact with a large number of cellular targets, many of which are involved in regulating diverse functions such as cell cycle regulation, transcription, differentiation and apoptosis. However both E6 and E7 are normally present at low levels within the virally infected cell, and how all these interactions are achieved and regulated has, until recently, been unclear. We have found that both E6 and E7 are subject to differential phosphorylation, the net results of which regulate their abilities to interact with some of their respective target proteins. In the case of E6, phosphorylation by Protein Kinase A (PKA) negatively regulates its ability to interact with the Discs Large (Dlg) tumour suppressor. In the case of E7, phosphorylation by Casein Kinase II (CKII) significantly increases its ability to interact with the TATA Box Binding Protein (TBP). Further, CKII regulation of E7 appears to vary during the cell cycle, therefore this provides a means of specifically targeting E7 to a given substrate at a given point within the cell cycle. This differential regulation of E6 and E7 by phosphorylation thus provides specificity to a diverse set of protein-protein interactions.
Massimi
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International Centre for Genetic Engineering and Biotechnology, Trieste, Italy.
Pim
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Kühne
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Banks
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D000818:Animals; D047390:Casein Kinase II; D002453:Cell Cycle; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004249:DNA Damage; D005786:Gene Expression Regulation; D006801:Humans; D007668:Kidney / Q000378:metabolism; D009856:Oncogene Proteins, Viral / Q000378:metabolism*; D050725:Papillomavirus E7 Proteins; D010766:Phosphorylation; D011233:Precipitin Tests; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D051381:Rats; D012097:Repressor Proteins; D014407:Tumor Cells, Cultured
C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; C059731:oncogene protein E7, Human papillomavirus type 16; D047390:Casein Kinase II; D017346:Protein Serine-Threonine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases