Activation of c-Myc contributes to bovine papillomavirus type 1 E7-induced cell proliferation.
Inactivation of the tumor suppressor pRB by the human papillomavirus (HPV) oncoprotein E7 is a mechanism by which HPV promotes cell growth. The bovine papillomavirus type 1 (BPV-1) E7 does not bind pRB efficiently yet is required for full transformation of murine cells by BPV-1. In the present study, we investigated the mechanism of BPV-1 E7-induced cell proliferation. Our studies indicate that expression of BPV-1 E7 induces DNA synthesis and stimulates cells to enter S phase in quiescent cells. The induction of cell proliferation by BPV-1 E7 can occur in the retinoblastoma gene (Rb)-null cells, suggesting an Rb-independent mechanism. Consistent with this observation, BPV-1 E7 does not efficiently activate the transcription of the E2F family of transcription factors (E2F)-responsive promoters. Notably, c-Myc is able to induce cells to enter S phase in quiescent cells through an Rb/E2F-independent pathway. Significantly, c-Myc levels are increased in BPV-1 E7-expressing cells. Moreover, expression of a dominant negative c-Myc mutant inhibited BPV-1 E7-induced DNA synthesis. Consistent with the notion that c-Myc could down-regulate p27 and activate Cdk2, p27 level is decreased while both cyclin A and cyclin E-associated kinase activities are up-regulated in BPV-1 E7-expressing cells. These studies indicate an important role for c-Myc in BPV-1 E7-induced cell proliferation.
Fan
Xueli
X
Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605-2324, USA.
Liu
Yun
Y
Chen
Jason J
JJ
D000818:Animals; D001973:Bromodeoxyuridine / Q000494:pharmacology; D042846:CDC2-CDC28 Kinases / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division; D019925:Cyclin A / Q000096:biosynthesis / Q000378:metabolism; D019927:Cyclin E / Q000096:biosynthesis / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004247:DNA / Q000378:metabolism; D015536:Down-Regulation; D005434:Flow Cytometry; D015151:Immunoblotting; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D041681:NIH 3T3 Cells; D009856:Oncogene Proteins, Viral / Q000378:metabolism*; D010957:Plasmids / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016196:S Phase; D015533:Transcriptional Activation; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D015854:Up-Regulation
C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D019925:Cyclin A; D019927:Cyclin E; D009856:Oncogene Proteins, Viral; D016271:Proto-Oncogene Proteins c-myc; D016160:Retinoblastoma Protein; D025521:Tumor Suppressor Proteins; C075621:oncogene protein E7, Bovine papillomavirus type 1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004247:DNA; D008156:Luciferases; D042846:CDC2-CDC28 Kinases; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D001973:Bromodeoxyuridine