Differential phosphorylation of the HPV-16 E7 oncoprotein during the cell cycle.

The human papillomavirus type 16 encodes two principal oncoproteins, E6 and E7. The E7 protein has been shown to deregulate the cell cycle through interactions with a variety of proteins involved in cell cycle control and transcriptional regulation. These activities result in E7 being able to cooperate with activated oncogenes in the transformation of primary rodent cells, and with the viral E6 protein during human keratinocyte immortalization. Although a large number of activities have been ascribed to the E7 protein, little is known about its regulation during the cell cycle. We have performed a series of studies to investigate potential changes in E7 phosphorylation during the cell cycle and we show that E7 is indeed differentially phosphorylated. Casein kinase II is the principal kinase during the early part of the cell cycle, but this activity decreases rapidly as cells progress toward S phase. In addition, E7 is transiently phosphorylated at Ser71 in S phase by another, as yet unknown, kinase. These results demonstrate differential regulation of the E7 protein during the cell cycle that most likely represents a means of providing specificity to E7's activities.