Interactions with pocket proteins contribute to the role of human papillomavirus type 16 E7 in the papillomavirus life cycle.
Human papillomaviruses (HPVs), most commonly the HPV16 genotype, are the principle etiological determinant for cervical cancer, a common cancer worldwide resulting in over 200,000 deaths annually. The oncogenic properties of HPVs are attributable in part to the virally encoded protein E7, best known for its ability to bind to and induce the degradation of the retinoblastoma tumor suppressor, pRb, and related "pocket proteins" p107 and p130. Previously, we defined a role for E7 in the productive stage of the HPV16 life cycle, which takes place in stratified squamous epithelia. HPV perturbs the normal processes of cell growth and differentiation of stratified squamous epithelia. HPVs reprogram cells to support continued DNA synthesis and inhibit their differentiation in the suprabasal compartment of the epithelia, where cells normally have withdrawn from the cell cycle and initiated a well-defined pattern of terminal differentiation. These virus-induced perturbations, which contribute to the production of progeny HPVs, are dependent on E7. In this study, we define the mechanism of action by which E7 contributes to the productive stage of the HPV16 life cycle. We found that the ability of HPV16 to reprogram suprabasal cells to support DNA synthesis correlates with E7's ability to bind pocket proteins but not its ability to induce their degradation. In contrast, the ability of HPV16 to perturb differentiation correlated with both E7's binding to and degradation of pocket proteins. These data indicate that different hallmarks of the productive stage of the HPV16 life cycle rely upon different sets of requirements for E7.
Collins
Asha S
AS
McArdle Laboratory for Cancer Research, University of Wisconsin, 1400 University Ave., Madison, WI 53706, USA.
Nakahara
Tomomi
T
Do
Anh
A
Lambert
Paul F
PF
D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D004279:DNA, Viral / Q000096:biosynthesis; D004847:Epithelial Cells / Q000821:virology; D006801:Humans; D008018:Life Cycle Stages; D027383:Papillomaviridae / Q000235:genetics / Q000254:growth & development / Q000378:metabolism / Q000502:physiology*; D014764:Viral Proteins / Q000378:metabolism
D004279:DNA, Viral; D014764:Viral Proteins